4-hydroxy-3-(heteroaryl)pyridine-2-one apj agonists

ABSTRACT

The present invention provides compounds of Formula (I): 
     
       
         
         
             
             
         
       
     
     wherein all variables are as defined in the specification, and compositions comprising any of such novel compounds. These compounds are APJ agonists which may be used as medicaments.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.15/990,855, filed May 29, 2018 (now allowed), which is a divisional ofU.S. application Ser. No. 15/171,276, filed Jun. 2, 2016 (now U.S. Pat.No. 10,011,594), which is entitled to priority pursuant to 35 U.S.C. §119(e) to U.S. provisional patent application No. 62/170,215, filed Jun.3, 2015, which are incorporated herein in their entirety.

FIELD OF THE INVENTION

The present invention provides novel4-hydroxyl-3-(heteroaryl)pyridine-2-one compounds, and their analoguesthereof, which are APJ agonists, compositions containing them, andmethods of using them, for example, for the treatment or prophylaxis ofheart failure, atherosclerosis, ischemic heart disease and relatedconditions.

BACKGROUND OF THE INVENTION

Heart failure (HF) and related complications constitute major healthburden in developed countries with an estimated prevalence of 5,700,000in the United States alone (Roger, V. L. et al., Circulation,125(1):e2-e220 (2012)). Despite considerable advances in recent twodecades, the prognosis remains very poor, with survival rates of only˜50% within 5-years of diagnosis (Roger, V. L. et al., JAMA,292(3):344-350 (2004)). In addition to poor survival, the impairedquality of life and recurrent hospitalizations constitute clear unmetmedical need for development of novel treatment options.

HF is a clinical syndrome characterized by the inability of the heart todeliver sufficient supply of blood and oxygen to meet the metabolicdemands of organs in the body. Main symptoms associated with HF includeshortness of breath due to pulmonary edema, fatigue, reduced toleranceto exercise and lower extremity edemas. The etiology of HF is highlycomplex with multiple associated risk factors and potential causes.

Among the leading causes of HF are coronary artery disease and cardiacischemia, acute myocardial infarction, intrinsic cardiomyopathies andchronic uncontrolled hypertension. HF can develop either acutely(functional impairment post myocardial infarction) or as a chroniccondition, characterized by long-term maladaptive cardiac tissueremodeling, hypertrophy and cardiac dysfunction (for example due touncontrolled long-term hypertension). According to the diagnosticcriteria and type of ventricular dysfunction, HF is classified to twomajor groups, HF with “reduced ejection fraction” (HFrEF) or HF with“preserved ejection fraction” (HFpEF). Both types are associated withsimilar signs and symptoms, but differ in the type of ventricularfunctional impairment (Borlaug, B. A. et al., Eur. Heart 32(6):670-679(2011)).

APJ receptor (APLNR) and its endogenous peptidic ligand apelin have beenimplicated as important modulators of cardiovascular function andcandidates for therapeutic intervention in HF (for review see Japp, A.G. et al., Biochem. Pharmacol., 75(10):1882-1892 (2008)).

Accumulated evidence from preclinical disease models and human heartfailure patients have implicated apelin and APJ agonism as beneficial inthe setting of HF. Mice lacking Apelin or APJ gene have impaired myocytecontractility (Chaco, D. N. et al., Am. J Physiol, Heart Circ. Physiol.,297(5):H1904-H1913 (2009)). Apelin knockout (KO) mice developprogressive cardiac dysfunction with aging and are more susceptible toHF in the model of trans-aortic constriction (TAC) (Kuba, K. et al.,Circ. Res., 101(4):e32-42 (2007)). The functional impairment in chronicHF is a result of prolonged demand on the heart and is associated withmaladaptive cardiac remodeling, manifested by the cardiac hypertrophy,increased inflammation and interstitial fibrosis which eventually leadto decrease in cardiac performance.

Acute administration of apelin increases cardiac output in rodents undernormal conditions and also in models of heart failure (Berry, M. F.,Circulation, 110(11 Suppl. 1):II187-II193 (2004)). Increased cardiacoutput is a result of direct augmentation of cardiac contractility andreduced peripheral vascular resistance in the arterial and venous beds(Ashley, E. A., Cardiovasc. Res., 65(1):73-82 (2005)). Reduction in thevascular resistance leads to lower pre-load and after-load on the heartand thus lesser work load (Cheng, X. et al., Eur. J. Pharmacol.,470(3):171-175 (2003)). Similar to rodent studies, acute infusion ofapelin to healthy human subjects and patients with heart failureproduces similar hemodynamic responses with increased cardiac output andincreased vasodilatory response in peripheral and coronary arteries(Japp, A. G. et al., Circulation, 121(16):1818-1827 (2010)).

The mechanisms underlying inotropic action of apelin are not wellunderstood, but appear to be distinct from clinically used β₁-adrenergicagonists (dobutamine) due to lack of increase in heart rate. Thevasodilatory action of apelin is primarily mediated via endothelialnitric oxide synthase pathways (Tatemoto, K., Regul. Pept.,99(2-3):87-92 (2001)). Apelin is induced under hypoxic conditions,promotes angiogenesis and has been shown to limit the infarct size inischemia-reperfusion models (Simpkin, J. C., Basic Res. Cardiol.,102(6):518-528 (2007)).

In addition to aforementioned studies evaluating acute administration ofapelin, several studies have clearly demonstrated beneficial effects ofprolonged administration of apelin in a number of chronic rodent modelsof HF, including the angiotensin II model, TAC model and rat Dahlsalt-sensitive model (Siddiquee, K. et al., J. Hypertens., 29(4):724-731(2011); Scimia, M. C. et al., Nature, 488(7411):394-398 (2012); Koguchi,W. et al., Circ. J., 76(1):137-144 (2012)). In these studies, prolongedapelin infusion reduced cardiac hypertrophy and cardiac fibrosis, andwas associated with improvement in cardiac performance.

Genetic evidence is also emerging that polymorphisms in the APJ gene areassociated with slower progression of HF (Sarzani, R. et al., J. Card.Fail., 13(7):521-529 (2007)). Importantly, while expression of APJ andapelin can be reduced or vary considerably with HF progression, thecardiovascular hemodynamic effects of apelin are sustained in patientswith developed HF and receiving standard of care therapy (Japp, A. G. etal., Circulation, 121(16):1818-1827 (2010)).

In summary, there is a significant amount of evidence to indicate thatAPJ receptor agonism plays a cardioprotective role in HF and would be ofpotential benefit to HF patients. Apelin's very short half life incirculation limits its therapeutic utility, and consequently, there is aneed for APJ receptor agonists with improved pharmacokinetic andsignaling profile while maintaining or enhancing the beneficial effectsof endogenous APJ agonist apelin.

SUMMARY OF THE INVENTION

The present invention provides 4-hydroxylpyridine-2-one compounds, andtheir analogues thereof, which are useful as APJ agonists, includingstereoisomers, tautomers, pharmaceutically acceptable salts, or solvatesthereof.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, or solvates thereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, or solvates thereof.

The compounds of the invention may be used in the treatment and/orprophylaxis of multiple diseases or disorders associated with APJ, suchas heart failure, coronary artery disease, cardiomyopathy, diabetes andrelated conditions including but not limited to acute coronary syndrome,myocardial ischemia, hypertension, pulmonary hypertension, coronaryvasospasm, cerebral vasospasm, ischemia/reperfusion injury, angina,renal disease, metabolic syndrome and insulin resistance.

The compounds of the invention may be used in therapy.

The compounds of the invention may be used for the manufacture of amedicament for the treatment and/or prophylaxis of multiple diseases ordisorders associated with APJ.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore other agent(s).

Other features and advantages of the invention will be apparent from thefollowing detailed description and claims.

DETAILED DESCRIPTION OF THE INVENTION I. Compounds of the Invention

In a first aspect, the present disclosure provides, inter alia, acompound of Formula (I):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, wherein:

-   alk is C₁₋₆ alkyl substituted with 0-5 R^(e);-   ring A is independently selected from:

-   ring B is independently selected from:

and 6-membered heteroaryl;

-   R¹ is independently selected from: halogen, NO₂, —(CH₂)_(n)OR^(b),    (CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a),    —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), —(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)OR^(b), —(CH₂)_(n)OC(═O)NR^(a)R^(a),    —(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)S(O)_(p)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)R^(c),    C₁₋₄ alkyl substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ carbocyclyl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R² is independently selected from: C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl substituted with 0-3 R^(e), and C₃₋₆ cycloalkyl    substituted with 0-3 R^(e); wherein the carbon atom except the one    attached to the ring of C₁₋₅ alkyl and the groups attached thereto    may be replaced by O, N, and S;-   R³ is independently selected from:    -   (1) —(CR⁴R⁴)_(n)C(═O)OC₁₋₄ alkyl substituted with 0-5 R^(e),    -   (2) —(CR⁴R⁴)_(n)NR^(a)R^(a),    -   (3) —(CR⁴R⁴)_(n)C(═O)NR^(a)R^(a),    -   (4) —(CR⁴R⁴)_(n)NR^(a)C(═O) C₁₋₄alkyl substituted with 0-5        R^(e),    -   (5) —(CR⁴R⁴)NR^(a)C(═O)(CR⁴R⁴)_(n)OC₁₋₄alkyl substituted with        0-5 R^(e),    -   (6) —(CR⁴R⁴)_(n)—R⁵,    -   (7) —(CR⁴R⁴)_(n)—OR⁵, and    -   (8) —(CR⁴R⁴)_(n)NR^(a)C(═O)(CR⁴R⁴)_(n)R⁵;-   R⁴ is independently selected from: H, halogen, NR^(a)R^(a), OC₁₋₄    alkyl, and C₁₋₄ alkyl; or R⁴ and R⁴ together with the carbon atom to    which they are both attached form C₃₋₆ cycloalkyl substituted with    0-5 R^(e);-   R⁵ is independently selected from: —(CH₂)_(n)—C₃₋₁₀ carbocycle and    —(CH₂)_(n)-heterocycle, each substituted with 0-3 R⁶;-   R⁶ is independently selected from: H, halogen, ═O, —(CH₂)_(n)OR^(b),    (CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a),    —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), —(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)OR^(b), —(CH₂)_(n)OC(═O)NR^(a)R^(a),    —(CH₂)_(n)C(═O)OR^(b), —(CH₂)S(O)_(p)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)R^(c),    C₁₋₅ alkyl substituted with 0-3 R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted    with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5    R^(e); or R^(a) and R^(a) together with the nitrogen atom to which    they are both attached form a heterocyclic ring substituted with 0-5    R^(e);-   R^(b) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted    with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5    R^(e);-   R^(c) is independently selected from C₁₋₆ alkyl substituted with 0-5    R^(e), C₂₋₆alkenyl substituted with 0-5 R^(e), C₂₋₆alkynyl    substituted with 0-5 R^(e), C₃₋₆carbocyclyl, and heterocyclyl;-   R^(e) is independently selected from C₁₋₆ alkyl substituted with 0-5    R_(f), C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl,    —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,    —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H,    —(CH₂)_(n)OR_(f), S(O)_(p)R^(f), C(═O)NR^(f)R^(f), NR^(f)C(═O)R^(f),    S(O)_(p)NR^(f)R^(f), NR^(f)S(O)_(p)R^(f), NR^(f)C(═O)OR,    OC(═O)NR^(f)R^(f) and —(CH₂)_(n)NR^(f)R^(f);-   R^(f) is independently selected from H, F, Cl, Br, CN, OH, C₁₋₅alkyl    (optimally substituted with halogen and OH), C₃₋₆ cycloalkyl, and    phenyl, or R^(f) and R^(f) together with the nitrogen atom to which    they are both attached form a heterocyclic ring optionally    substituted with C₁₋₄alkyl;-   n is independently selected from zero, 1, 2, and 3; and-   p is independently selected from zero, 1, and 2.

In a second aspect, the present disclosure provides a compound ofFormula (II):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, within the scope of the first aspect, wherein:

-   R¹ is independently selected from: F, Cl, Br,    -   NO₂, —(CH₂)_(n)OR^(b), —(CH₂)_(n)C(═O)R^(b),        —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)C(═O)NR^(a)R^(a),        —(CH₂)_(n)NR^(a)C(═O)R^(b), C₁₋₄ alkyl substituted with 0-3        R^(e) and C₃₋₆ cycloalkyl substituted with 0-3 R^(e);-   R² is independently selected from: C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, and C₃₋₆ cycloalkyl; wherein the carbon atom    except the one attached to the ring of C₁₋₅ alkyl and the groups    attached thereto are replaced by O, N, and S;-   R³ is independently selected from:    -   (1) —(CR⁴R⁴)_(n)C(═O)OC₁₋₄ alkyl substituted with 0-5 R^(e),    -   (2) —(CR⁴R⁴)_(n)NR^(a)R^(a),    -   (3) —(CR⁴R⁴)_(n)C(═O)NR^(a)R^(a),    -   (4) —(CR⁴R⁴)_(n)NR^(a)C(═O) C₁₋₄alkyl substituted with 0-5        R^(e),    -   (5) —(CR⁴R⁴)_(n)NR^(a)C(═O)(CR⁴R⁴)_(n)OC₁₋₄alkyl substituted        with 0-5 R^(e),    -   (6) —(CR⁴R⁴)_(n)—R⁵,    -   (7) —(CR⁴R⁴)_(n)—OR⁵, and    -   (8) —(CR⁴R⁴)_(n)NR^(a)C(═O)(CR⁴R⁴)_(n)R⁵;-   R⁴ is independently selected from: H, F, Cl, NR^(a)R^(a), OC₁₋₄    alkyl, and C₁₋₄ alkyl; or R⁴ and R⁴ together with the carbon atom to    which they are both attached form C₃₋₆ cycloalkyl substituted with    0-5 R^(e);-   R⁵ is independently selected from: —(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆    cycloalkyl and —(CH₂)_(n)-heterocycle, each substituted with 0-3 R⁶;-   R⁶ is independently selected from: H, F, Cl, Br, —OR^(b),    -   ═O, —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),        —(CH₂)_(n)NR^(a)R^(a), CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), C₁₋₄        alkyl substituted with 0-3 R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl        substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl        substituted with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),    and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) and    R^(a) together with the nitrogen atom to which they are both    attached form a heterocyclic ring substituted with 0-5 R^(e);-   R^(b) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted    with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5    R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl substituted with 0-5    R_(f), C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl,    —(CH₂)_(n)—C₄₋₆    -   heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br,        CN, NO₂, ═O, CO₂H, —(CH₂)_(n)OR_(f), S(O)_(p)R^(f),        C(═O)NR^(f)R^(f), NR^(f)C(═O)R^(f), S(O)_(p)NR^(f)R^(f),        NR^(f)S(O)_(p)R^(f), NR^(f)C(═O)OR^(f), OC(═O)NR^(f)R^(f) and        —(CH₂)_(n)NR^(f)R^(f);-   R^(f) is independently selected from H, F, Cl, Br, CN, OH, C₁₋₅alkyl    (optimally substituted with halogen and OH), C₃₋₆ cycloalkyl, and    phenyl;-   n is independently selected from zero, 1, 2, and 3; and-   p is independently selected from zero, 1, and 2.

In a third aspect, the present disclosure provides a compound of Formula(III):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, within the scope of the first or second aspect,wherein:

-   R¹ is independently selected from: F, Cl, OH, and OC₁₋₄ alkyl;-   R^(1a) is independently selected from: F, Cl, and C₁₋₂ alkyl;-   R² is independently selected from: C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, and C₃₋₆ cycloalkyl and CH₂O(CH₂)₁₋₃CH₃;-   R³ is independently selected from:    -   (1) —(CR⁴R⁴)_(n)C(═O)OC₁₋₄ alkyl substituted with 0-5 R^(e),    -   (2) —(CR⁴R⁴)_(n)NR^(a)R^(a),    -   (3) —(CR⁴R⁴)_(n)C(═O)NR^(a)R^(a),    -   (4) —(CR⁴R⁴)_(n)NR^(a)C(═O) C₁₋₄alkyl substituted with 0-5        R^(e),    -   (5) —(CR⁴R⁴)_(n)NR^(a)C(═O)(CR⁴R⁴)_(n)OC₁₋₄alkyl substituted        with 0-5 R^(e),    -   (6) —(CR⁴R⁴)_(n)—R⁵,    -   (7) —(CR⁴R⁴)_(n)—OR⁵, and    -   (8) —(CR⁴R⁴)_(n)NR^(a)C(═O)(CR⁴R⁴)_(n)R⁵;-   R⁴ is independently selected from: H, F, Cl, NR^(a)R^(a), OC₁₋₄    alkyl, and C₁₋₄ alkyl; or R⁴ and R⁴ together with the carbon atom to    which they are both attached form C₃₋₆ cycloalkyl substituted with    0-5 R^(e);-   R⁵ is independently selected from: —(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆    cycloalkyl and —(CH₂)_(n)-heterocycle, each substituted with 0-3 R⁶;-   R⁶ is independently selected from: H, F, Cl, Br, —OR^(b),    -   ═O, —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),        —(CH₂)_(n)NR^(a)R^(a), CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), C₁₋₄        alkyl substituted with 0-3 R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl        substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl        substituted with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),    and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) and    R^(a) together with the nitrogen atom to which they are both    attached form a heterocyclic ring substituted with 0-5 R^(e);-   R^(b) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted    with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5    R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl (optionally    substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆    cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,    —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H; and-   n is independently selected from zero, 1, 2, and 3.

In a fourth aspect, the present disclosure provides a compound ofFormula (III), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of any of thefirst, second and third aspects, wherein:

-   R³ is independently selected from:    -   (1) —(CR⁴R⁴)_(n)—R⁵,    -   (2) —(CR⁴R⁴)_(n)—OR⁵, and    -   (3) —(CR⁴R⁴)_(n)NR^(a)C(═O)(CR⁴R⁴)_(n)R⁵;-   R⁴ is independently selected from: H, F, Cl, N(CH₃)₂, OCH₃, and CH₃;    or R⁴ and R⁴ together with the carbon atom to which they are both    attached form cyclopropyl;-   R⁵ is independently selected from:

-   R⁶ is independently selected from: H, F, Cl, Br, —OCH₃, —OCF₃, ═O,    CN, CH₃, CF₃—(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted    with 0-3 R^(e),    -   and —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(6a) is independently selected from: H, CH₃, aryl substituted with    0-3 R^(e), and heterocyclyl substituted with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),    and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl (optionally    substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆    cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,    —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H; and-   n is independently selected from zero, 1, 2, and 3.

In a fifth aspect, the present disclosure provides a compound of Formula(III), or a stereoisomer, a tautomer, a pharmaceutically acceptablesalt, or a solvate thereof, within the scope of any of the first, secondand third aspects, wherein:

-   R³ is independently selected from:    -   (1) —(CR⁴R⁴)_(n)NR^(a)R^(a),    -   (2) —(CR⁴R⁴)_(n)C(═O)NR^(a)R^(a),-   R⁴ is independently selected from: H, F, Cl, N(CH₃)₂, OCH₃, and CH₃;    or R⁴ and R⁴ together with the carbon atom to which they are both    attached form C₃₋₆ cycloalkyl substituted with 0-5 R^(e);-   R⁶ is independently selected from: H, F, Cl, Br, —OCH₃, —OCF₃, ═O,    CN, CH₃, CF₃—(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted    with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-3    R^(e);-   R^(6a) is independently selected from: H, CH₃, aryl substituted with    0-3 R^(e), and heterocyclyl substituted with 0-3 R^(e);-   R^(a) and R^(a) together with the nitrogen atom to which they are    both attached form a heterocyclic ring substituted with 0-5 R^(e),    wherein the heterocyclic ring is selected from:

-   R^(e) is independently selected from C₁₋₆ alkyl (optionally    substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆    cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,    —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, =O, CO₂H; and-   n is independently selected from zero, 1, 2, and 3.

In a sixth aspect, the present disclosures provides a compound ofFormula (III), or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof, within the scope of any of thefirst, second and third aspects, wherein:

-   R¹ is independently selected from: F, Cl, OH, and OC₁₋₄ alkyl;-   R^(1a) is independently selected from: F, Cl, and C₁₋₂ alkyl;-   R² is independently selected from: C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, and C₃₋₆ cycloalkyl; and CH₂O(CH₂)₁₋₃CH₃;-   R³ is independently selected from:    -   (1) —(CH₂)_(n)C(═O)OC₁₋₄ alkyl substituted with 0-3 R^(e),    -   (2) —(CH₂)_(n)NR^(a)R^(a),    -   (3) —(CH₂)_(n)C(═O)NR^(a)R^(a),    -   (4) —(CH₂)NR^(a)C(═O) C₁₋₄alkyl substituted with 0-3 R^(e), and    -   (5) —(CH₂)_(n)NR^(a)C(═O)(CR⁴R⁴)_(n)OC₁₋₄alkyl substituted with        0-3 R^(e);-   R⁴ is independently selected from: H, F, Cl, NR^(a)R^(a), OC₁₋₄    alkyl, and C₁₋₄ alkyl;-   R⁵ is independently selected from: —(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆    cycloalkyl and —(CH₂)_(n)-heterocycle, each substituted with 0-3 R⁶;-   R⁶ is independently selected from: H, F, Cl, Br, —OCH₃, —OCF₃, =O,    CN, CH₃, CF₃—(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted    with 0-3 R^(e),    -   and —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),    and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl (optionally    substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆    cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,    —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H; and-   n is independently selected from zero, 1, 2, and 3.

In a seventh aspect, the present disclosures provides a compound ofFormula (IV):

or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof, within the scope of the first and second aspects,wherein:

-   R¹ is independently selected from: —CH₂OH, —OCH₃, —OCF₃, OCH₂Ph,    —C(═O)NR^(a)R^(a), NR^(a)R^(a), CH₃, CH₂CH₃, CH(CH₃)₂, and    cyclopropyl;-   R² is independently selected from: C₁₋₄ alkyl substituted with 0-3    R^(e); C₂₋₄ alkenyl, C₃₋₆ cycloalkyl, and CH₂O(CH₂)₁₋₃CH₃;-   R³ is independently selected from:    -   (1) —(CR⁴R⁴)_(n)C(═O)OC₁₋₄ alkyl substituted with 0-3 R^(e),    -   (2) —(CR⁴R⁴)_(n)NR^(a)R^(a),    -   (3) —(CR⁴R⁴)_(n)C(═O)NR^(a)R^(a),    -   (4) —(CR⁴R⁴)_(n)NR^(a)C(═O) C₁₋₄alkyl substituted with 0-3        R^(e),    -   (5) —(CR⁴R⁴)_(n)NR^(a)C(═O)(CR⁴R⁴)_(n)OC₁₋₄alkyl substituted        with 0-3 R^(e),    -   (6) —(CR⁴R⁴)_(n)—R⁵,    -   (7) —(CR⁴R⁴)_(n)—OR⁵, and    -   (8) —(CR⁴R⁴)_(n)NR^(a)C(═O)(CR⁴R⁴)_(n)R⁵;-   R⁴ is independently selected from: H, F, Cl, NR^(a)R^(a), OC₁₋₄    alkyl, and C₁₋₄ alkyl;-   R⁵ is independently selected from: aryl, C₃₋₆ cycloalkyl and    heterocycle, each substituted with 0-3 R⁶;-   R⁶ is independently selected from: H, F, Cl, Br, —OR^(b),    -   ═O, —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),        —(CH₂)_(n)NR^(a)R^(a),    -   CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), C₁₋₄ alkyl substituted with 0-3        R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5    -   R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a)        and R^(a) together with the nitrogen atom to which they are both        attached form a heterocyclic ring substituted with 0-5 R^(e);-   R^(b) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted    with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5    R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl (optionally    substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆    cycloalkyl, —(CH₂)_(n)—C₄₋₆    -   heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br,        CN, NO₂, ═O, CO₂H; and-   n is independently selected from zero, 1, 2, and 3.

In an eighth aspect, the present invention provides a compound selectedfrom the exemplified examples or a stereoisomer, a tautomer, apharmaceutically acceptable salt, or a solvate thereof.

In another aspect, the present invention provides compounds of Formula(I):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein:alk is C₁₋₆ alkyl substituted with 0-5 R^(e);ring A is independently selected from:

ring B is independently selected from:

and 6-membered heteroaryl;

-   R¹ is independently selected from: H, halogen, NO₂,    —(CH₂)_(n)OR^(b), (CH₂)_(n)S(O)R^(e), —(CH₂)_(n)C(═O)R^(b),    —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), —(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)OR^(b), —(CH₂)_(n)OC(═O)NR^(a)R^(a),    —(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)S(O)_(p)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)R^(c),    C₁₋₄ alkyl substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ carbocyclyl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R² is independently selected from: C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl substituted with 0-3 R^(e), and C₃₋₆ cycloalkyl    substituted with 0-3 R^(e); provided when R² is C₁₋₅ alkyl, the    carbon atom except the one attached directly to the pyridine ring    may be replaced by O, N, and S;-   R³ is independently selected from:    -   (1) —(CR⁴R⁴)_(r)C(═O)OC₁₋₄ alkyl substituted with 0-5 R^(e),    -   (2) —(CR⁴R⁴)_(r)NR^(a)R^(a),    -   (3) —(CR⁴R⁴)_(r)C(═O)NR^(a)R^(a),    -   (4) —(CR⁴R⁴)_(r)NR^(a)C(═O)C₁₋₄alkyl substituted with 0-5 R^(e),    -   (5) —(CR⁴R⁴)_(r)NR^(a)C(═O)(CR⁴R⁴)_(n)OC₁₋₄alkyl substituted        with 0-5 R^(e),    -   (6) —(CR⁴R⁴)_(r)—R⁵,    -   (7) —(CR⁴R⁴)_(r)—OR⁵,    -   (8) —(CR⁴R⁴)_(r)NR^(a)C(═O)(CR⁴R⁴)_(n)R⁵, and    -   (9) —(CR⁴R⁴)_(r)C(═O)NR^(a)(CR⁴R⁴)_(n)R⁵;-   R⁴ is independently selected from: H, halogen, NR^(a)R^(a), OC₁₋₄    alkyl, and C₁₋₄ alkyl; or    -   R⁴ and R⁴ together with the carbon atom to which they are both        attached form C₃₋₆ cycloalkyl substituted with 0-5 R^(e);-   R⁵ is independently selected from: —(CH₂)_(n)—C₃₋₁₀ carbocycle and    —(CH₂)_(n)-heterocycle, each substituted with 0-3 R⁶;-   R⁶ is independently selected from: H, halogen, ═O, —(CH₂)_(n)OR^(b),    -   (CH₂)_(n)S(O)_(p)R_(e), —(CH₂)_(n)C(═O)R^(b),        —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),        —(CH₂)_(n)NR^(a)C(═O)R^(b), —(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a),        —(CH₂)_(n)NR^(a)C(═O)OR^(b), —(CH₂)_(n)OC(═O)NR^(a)R^(a),        —(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)S(O)_(p)NR^(a)R^(a),        —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a),        —(CH₂)_(n)NR^(a)S(O)_(p)R^(e), C₁₋₅ alkyl substituted with 0-3        R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted    with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5    R^(e); or R^(a) and R^(a) together with the nitrogen atom to which    they are both attached form a heterocyclic ring substituted with 0-5    R^(e);-   R^(b) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted    with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5    R^(e);-   R^(c) is independently selected from C₁₋₆ alkyl substituted with 0-5    R^(e), C₂₋₆alkenyl substituted with 0-5 R^(e), C₂₋₆alkynyl    substituted with 0-5 R^(e), C₃₋₆carbocyclyl, and heterocyclyl;-   R^(e) is independently selected from C₁₋₆ alkyl substituted with 0-5    R_(f), C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl,    —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,    —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H,    —(CH₂)_(n)OR_(f), S(O)_(p)R_(f), C(═O)NR^(f)R^(f), NR^(f)C(═O)R^(f),    S(O)_(p)NR^(f)R^(f), NR^(f)S(O)_(p)R^(f), NR^(f)C(═O)OR^(f),    OC(═O)NR^(f)R^(f) and —(CH₂)_(n)NR^(f)R^(f);-   R^(f) is independently selected from H, F, Cl, Br, CN, OH, C₁₋₅alkyl    (optimally substituted with halogen and OH), C₃₋₆ cycloalkyl, and    phenyl, or R^(f) and R^(f) together with the nitrogen atom to which    they are both attached form a heterocyclic ring optionally    substituted with C₁₋₄alkyl;-   n is independently selected from zero, 1, 2, and 3;-   r is independently selected from zero, 1, 2, and 3; and-   p is independently selected from zero, 1, and 2.

In another aspect, the present invention provides compounds of Formula(I), or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein:

-   alk is C₁₋₆ alkyl substituted with 0-5 R^(e);-   ring A is independently selected from:

-   ring B is independently selected from:

and 6-membered heteroaryl;

-   R¹ is independently selected from: H, halogen, NO₂,    —(CH₂)_(n)OR^(b), (CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b),    —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), —(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)OR^(b), —(CH₂)_(n)OC(═O)NR^(a)R^(a),    —(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)S(O)_(p)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)R^(c),    C₁₋₄ alkyl substituted with 0-3 R^(e), —(CH₂)_(n)—C₃₋₆ carbocyclyl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R² is independently selected from: C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl substituted with 0-3 R^(e), and C₃₋₆ cycloalkyl    substituted with 0-3 R^(e); provided when R² is C₁₋₅ alkyl, the    carbon atom except the one attached directly to the pyridine ring    may be replaced by O, N, and S;-   R³ is independently selected from:    -   (1) —(CR⁴R⁴)_(r)C(═O)OC₁₋₄ alkyl substituted with 0-5 R^(e),    -   (2) —(CR⁴R⁴)_(r)NR^(a)R^(a),    -   (3) —(CR⁴R⁴)_(r)C(═O)NR^(a)R^(a),    -   (4) —(CR⁴R⁴)_(r)NR^(a)C(═O)C₁₋₄alkyl substituted with 0-5 R^(e),    -   (5) —(CR⁴R⁴)_(r)NR^(a)C(═O)(CR⁴R⁴)_(n)OC₁₋₄alkyl substituted        with 0-5 R^(e),    -   (6) —(CR⁴R⁴)_(r)—R⁵,    -   (7) —(CR⁴R⁴)_(r)—OR⁵,    -   (8) —(CR⁴R⁴)_(r)NR^(a)C(═O)(CR⁴R⁴)_(n)R⁵, and    -   (9) —(CR⁴R⁴)_(r)C(═O)NR^(a)(CR⁴R⁴)_(n)R⁵;-   R⁴ is independently selected from: H, halogen, NR^(a)R^(a), OC₁₋₄    alkyl, and C₁₋₄ alkyl; or R⁴ and R⁴ together with the carbon atom to    which they are both attached form C₃₋₆ cycloalkyl substituted with    0-5 R^(e);-   R⁵ is independently selected from: —(CH₂)_(n)—C₃₋₁₀ carbocycle and    —(CH₂)_(n)-heterocycle, each substituted with 0-3 R⁶;-   R⁶ is independently selected from: H, halogen, ═O, —(CH₂)_(n)OR^(b),    (CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a),    —(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)R^(b), —(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)C(═O)OR^(b), —(CH₂)_(n)OC(═O)NR^(a)R^(a),    —(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)S(O)_(p)NR^(a)R^(a),    —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)R^(c),    C₁₋₅ alkyl substituted with 0-3 R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl    substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl substituted    with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted    with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5    R^(e); or R^(a) and R^(a) together with the nitrogen atom to which    they are both attached form a heterocyclic ring substituted with 0-5    R^(e);-   R^(b) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted    with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-5    R^(e);-   R^(c) is independently selected from C₁₋₆ alkyl substituted with 0-5    R^(e), C₂₋₆alkenyl substituted with 0-5 R^(e), C₂₋₆alkynyl    substituted with 0-5 R^(e), C₃₋₆carbocyclyl, and heterocyclyl;-   R^(e) is independently selected from C₁₋₆ alkyl substituted with 0-5    R_(f), C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl,    —(CH₂)_(n)—C₄₋₆    -   heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br,        CN, NO₂, =O, CO₂H, —(CH₂)_(n)OR_(f), S(O)_(p)R^(f),        C(═O)NR^(f)R^(f), NR^(f)C(═O)R_(f), S(O)_(p)NR^(f)R^(f),        NR^(f)S(O)_(p)R^(f), NR^(f)C(═O)OR^(f), OC(═O)NR^(f)R^(f) and        —(CH₂)_(n)NR^(f)R^(f);-   R^(f) is independently selected from H, F, Cl, Br, CN, OH, C₁₋₅alkyl    (optimally substituted with halogen and OH), C₃₋₆ cycloalkyl, and    phenyl, or R^(f) and R^(f) together with the nitrogen atom to which    they are both attached form a heterocyclic ring optionally    substituted with C₁₋₄alkyl;-   n is independently selected from zero, 1, 2, and 3;-   r is independently selected from zero, 1, 2, and 3; and-   p is independently selected from zero, 1, and 2.

In another aspect, the present invention provides compounds of Formula(II):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof,wherein:

-   R¹ is independently selected from: F, Cl, Br,    -   NO₂, —(CH₂)_(n)OR^(b), —(CH₂)_(n)C(═O)R^(b),        —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)C(═O)NR^(a)R^(a),        —(CH₂)_(n)NR^(a)C(═O)R^(b), C₁₋₄ alkyl substituted with 0-3        R^(e) and C₃₋₆ cycloalkyl substituted with 0-3 R^(e);-   R² is independently selected from: C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, and C₃₋₆ cycloalkyl; provided when R² is C₁₋₅    alkyl, the carbon atom except the one attached directly to the    pyridine ring may be replaced by O, N, and S;-   R³ is independently selected from:    -   (1) —(CR⁴R⁴)_(r)C(═O)OC₁₋₄ alkyl substituted with 0-5 R^(e),    -   (2) —(CR⁴R⁴)_(r)NR^(a)R^(a),    -   (3) —(CR⁴R⁴)_(r)C(═O)NR^(a)R^(a),    -   (4) —(CR⁴R⁴)_(r)NR^(a)C(═O)C₁₋₄alkyl substituted with 0-5 R^(e),    -   (5) —(CR⁴R⁴)_(r)NR^(a)C(═O)(CR⁴R⁴)_(n)OC₁₋₄alkyl substituted        with 0-5 R^(e),    -   (6) —(CR⁴R⁴)_(r)—R⁵,    -   (7) —(CR⁴R⁴)_(r)—OR⁵,    -   (8) —(CR⁴R⁴)_(r)NR^(a)C(═O)(CR⁴R⁴)_(n)R⁵, and    -   (9) —(CR⁴R⁴)_(r)C(═O)NR^(a)(CR⁴R⁴)_(n)R⁵;-   R⁴ is independently selected from: H, F, Cl, NR^(a)R^(a), OC₁₋₄    alkyl, and C₁₋₄ alkyl; or R⁴ and R⁴ together with the carbon atom to    which they are both attached form C₃₋₆ cycloalkyl substituted with    0-5 R^(e);-   R⁵ is independently selected from: —(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆    cycloalkyl and —(CH₂)_(n)-heterocycle, each substituted with 0-3 R⁶;-   R⁶ is independently selected from: H, F, Cl, Br, —OR^(b),    -   ═O, —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),        —(CH₂)_(n)NR^(a)R^(a),    -   CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂)_(n)S(O)_(p)NR^(a)R^(a),        C₁₋₄ alkyl substituted with 0-3 R^(e), (CH₂)_(n)—C₃₋₆        carbocyclyl substituted with 0-3 R^(e), and        —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5    -   R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a)        and R^(a) together with the nitrogen atom to which they are both        attached form a heterocyclic ring substituted with 0-5 R^(e);-   R^(b) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5    -   R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl substituted with 0-5    R_(f), C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl,    —(CH₂)_(n)—C₄₋₆    -   heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br,        CN, NO₂, ═O, CO₂H, —(CH₂)_(n)OR_(f), S(O)_(p)R^(f),        C(═O)NR^(f)R^(f), NR^(f)C(═O)R^(f), S(O)_(p)NR^(f)R^(f),        NR^(f)S(O)_(p)R^(f), NR^(f)C(═O)OR^(f), OC(═O)NR^(f)R^(f) and        —(CH₂)_(n)NR^(f)R^(f);-   R^(f) is independently selected from H, F, Cl, Br, CN, OH, C₁₋₅alkyl    (optimally substituted with halogen and OH), C₃₋₆ cycloalkyl, and    phenyl;-   n is independently selected from zero, 1, 2, and 3;-   r is independently selected from 1, 2, and 3; and-   p is independently selected from zero, 1, and 2.

In another aspect, the present invention provides compounds of Formula(III):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvate, or prodrugs thereof,wherein:

-   R¹ is independently selected from: F, Cl, OH, and OC₁₋₄ alkyl;-   R^(1a) is independently selected from: F, Cl, and C₁₋₂ alkyl;-   R² is independently selected from: C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, and C₃₋₆ cycloalkyl and CH₂O(CH₂)₁₋₃CH₃;-   R³ is independently selected from:    -   (1) —(CR⁴R⁴)_(r)C(═O)OC₁₋₄ alkyl substituted with 0-5 R^(e),    -   (2) —(CR⁴R⁴)_(r)NR^(a)R^(a),    -   (3) —(CR⁴R⁴)_(r)C(═O)NR^(a)R^(a),    -   (4) —(CR⁴R⁴)_(r)NR^(a)C(═O) C₁₋₄alkyl substituted with 0-5        R^(e),    -   (5) —(CR⁴R⁴)_(r)NR^(a)C(═O)(CR⁴R⁴)_(n)OC₁₋₄alkyl substituted        with 0-5 R^(e),    -   (6) —(CR⁴R⁴)_(r)—R⁵,    -   (7) —(CR⁴R⁴)_(r)—OR⁵, and    -   (8) —(CR⁴R⁴)_(r)NR^(a)C(═O)(CR⁴R⁴)_(n)R⁵, and    -   (9) —(CR⁴R⁴)_(r)C(═O)NR^(a)(CR⁴R⁴)_(n)R⁵;-   R⁴ is independently selected from: H, F, Cl, NR^(a)R^(a), OC₁₋₄    alkyl, and C₁₋₄ alkyl; or R⁴ and R⁴ together with the carbon atom to    which they are both attached form C₃₋₆ cycloalkyl substituted with    0-5 R^(e);-   R⁵ is independently selected from: —(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆    cycloalkyl and —(CH₂)_(n)-heterocycle, each substituted with 0-3 R⁶;-   R⁶ is independently selected from: H, F, Cl, Br, —OR^(b),    -   ═O, —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),        —(CH₂)_(n)NR^(a)R^(a),    -   CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂)_(n)S(O)NR^(a)R^(a), C₁₋₄        alkyl substituted with 0-3 R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl        substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl        substituted with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5    -   R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a)        and R^(a) together with the nitrogen atom to which they are both        attached form a heterocyclic ring substituted with 0-5 R^(e);-   R^(b) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5    -   R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl (optionally    substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆    cycloalkyl, —(CH₂)_(n)—C₄₋₆    -   heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br,        CN, NO₂, =O, CO₂H; d-   n is independently selected from zero, 1, 2, and 3; and-   r is independently selected from 1, 2, and 3.

In another aspect, the present invention provides compounds of Formula(IIIa):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvate, or prodrugs thereof,wherein:

-   R¹ is independently selected from: F, Cl, OH, and OC₁₋₄ alkyl;-   R^(1a) is independently selected from: F, Cl, and C₁₋₂ alkyl;-   R² is independently selected from: C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, and C₃₋₆ cycloalkyl and CH₂O(CH₂)₁₋₃CH₃;-   R³ is independently selected from:    -   (1) —(CR⁴R⁴)_(r)C(═O)OC₁₋₄ alkyl substituted with 0-5 R^(e),    -   (2) —(CR⁴R⁴)_(r)NR^(a)R^(a),    -   (3) —(CR⁴R⁴)_(r)C(═O)NR^(a)R^(a),    -   (4) —(CR⁴R⁴)_(r)NR^(a)C(═O) C₁₋₄alkyl substituted with 0-5        R^(e),    -   (5) —(CR⁴R⁴)_(r)NR^(a)C(═O)(CR⁴R⁴)_(n)OC₁₋₄alkyl substituted        with 0-5 R^(e),    -   (6) —(CR⁴R⁴)—R⁵,    -   (7) —(CR⁴R⁴)_(r)—OR⁵, and    -   (8) —(CR⁴R⁴)_(r)NR^(a)C(═O)(CR⁴R⁴)_(n)R⁵, and    -   (9) —(CR⁴R⁴)_(r)C(═O)NR^(a)(CR⁴R⁴)_(n)R⁵;-   R⁴ is independently selected from: H, F, Cl, NR^(a)R^(a), OC₁₋₄    alkyl, and C₁₋₄ alkyl; or R⁴ and R⁴ together with the carbon atom to    which they are both attached form C₃₋₆ cycloalkyl substituted with    0-5 R^(e);-   R⁵ is independently selected from: —(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆    cycloalkyl and —(CH₂)_(n)-heterocycle, each substituted with 0-3 R⁶;-   R⁶ is independently selected from: H, F, Cl, Br, —OR^(b),    -   ═O, —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),        —(CH₂)_(n)NR^(a)R^(a), CN, —(CH₂)_(n)C(═O)NR^(a)R^(a),        —(CH₂)_(n)S(O)_(p)NR^(a)R^(a), C₁₋₄ alkyl substituted with 0-3        R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5    -   R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a)        and R^(a) together with the nitrogen atom to which they are both        attached form a heterocyclic ring substituted with 0-5 R^(e);-   R^(b) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5    -   R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl (optionally    substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆    cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl, —(CH₂)_(n)-aryl,    —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H; d-   n is independently selected from zero, 1, 2, and 3; and-   r is independently selected from 1, 2, and 3.

In another aspect, the present invention provides compounds of Formula(III), or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvate, or prodrugs thereof,wherein:

-   R³ is independently selected from:    -   (1) —(CR⁴R⁴)_(r)—R⁵,    -   (2) —(CR⁴R⁴)_(r)—OR⁵,    -   (3) —(CR⁴R⁴)_(r)NR^(a)C(═O)(CR⁴R⁴)_(n)R⁵, and    -   (4) —(CR⁴R⁴)_(r)C(═O)NR^(a)(CR⁴R⁴)_(n)R⁵;-   R⁴ is independently selected from: H, F, Cl, N(CH₃)₂, OCH₃, and CH₃;    or R⁴ and R⁴ together with the carbon atom to which they are both    attached form cyclopropyl;-   R⁵ is independently selected from:

-   R⁶ is independently selected from: H, F, Cl, Br, —OCH₃, —OCF₃, ═O,    —NR^(a)R^(a), CN, —S(O)₂NH₂, CH₃, CF₃—(CH₂)_(n)-aryl,    —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with 0-3 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R⁶ is independently selected from: H, CH₃, aryl substituted with 0-3    R^(e), and    -   heterocyclyl substituted with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5    -   R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl (optionally    substituted with F and Cl),    -   OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆    -   heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br,        CN, NO₂, ═O, CO₂H;-   n is independently selected from zero, 1, 2, and 3;-   r is independently selected from 1, 2, and 3; and-   other variables are as defined in Formula (III).

In another aspect, the present invention provides compounds of Formula(III), or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvate, or prodrugs thereof,wherein:

-   R³ is independently selected from:    -   (1) —(CR⁴R⁴)_(r)NR^(a)R^(a), and    -   (2) —(CR⁴R⁴)_(r)C(═O)NR^(a)R^(a),-   R⁴ is independently selected from: H, F, Cl, N(CH₃)₂, OCH₃, and CH₃;    or R⁴ and R⁴ together with the carbon atom to which they are both    attached form C₃₋₆ cycloalkyl substituted with 0-5 R^(e);-   R⁶ is independently selected from: H, F, Cl, Br, —OCH₃, —OCF₃, =O,    CN, —NR^(a)R^(a), —S(O)₂NH₂, —CH₃, CF₃—(CH₂)_(n)-aryl,    —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with 0-3 R^(e), and    —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(6a) is independently selected from: H, CH₃, aryl substituted with    0-3 R^(e), and heterocyclyl substituted with 0-3 R^(e);-   R^(a) and R^(a) together with the nitrogen atom to which they are    both attached form a heterocyclic ring substituted with 0-5 R^(e),    wherein the heterocyclic ring is selected from:

-   R^(e) is independently selected from C₁₋₆ alkyl (optionally    substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆    cycloalkyl, —(CH₂)_(n)—C₄₋₆    -   heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br,        CN, NO₂, =O, CO₂H;-   n is independently selected from zero, 1, 2, and 3;-   r is independently selected from 1, 2, and 3, and-   other variables are as defined in Formula (III).

In another aspect, the present invention provides compounds of Formula(III), or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvate, or prodrugs thereof,wherein:

-   R¹ is independently selected from: F, Cl, OH, and OC₁₋₄ alkyl;-   R^(1a) is independently selected from: F, Cl, and C₁₋₂ alkyl;-   R² is independently selected from: C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, and C₃₋₆ cycloalkyl; and CH₂O(CH₂)₁₋₃CH₃;-   R³ is independently selected from:    -   (1) —(CH₂)_(r)C(═O)OC₁₋₄ alkyl substituted with 0-3 R^(e),    -   (2) —(CH₂)_(r)NR^(a)R^(a),    -   (3) —(CH₂)_(r)C(═O)NR^(a)R^(a),    -   (4) —(CH₂)_(r)NR^(a)C(═O)C₁₋₄alkyl substituted with 0-3 R^(e),        and    -   (5) —(CH₂)_(r)NR^(a)C(═O)(CR⁴R⁴)_(n)OC₁₋₄alkyl substituted with        0-3 R^(e);-   R⁴ is independently selected from: H, F, Cl, NR^(a)R^(a), OC₁₋₄    alkyl, and C₁₋₄ alkyl;-   R⁵ is independently selected from: —(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆    cycloalkyl and —(CH₂)_(n)-heterocycle, each substituted with 0-3 R⁶;-   R⁶ is independently selected from: H, F, Cl, Br, —OCH₃, —OCF₃, =O,    CN, —NR^(a)R^(a), S(O)₂NH₂, CH₃, CF₃—(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆    cycloalkyl substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl    substituted with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5    -   R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl (optionally    substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆    cycloalkyl, —(CH₂)_(n)—C₄₋₆    -   heterocyclyl, —(CH₂)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN,        NO₂, =O, CO₂H;-   n is independently selected from zero, 1, 2, and 3; and-   r is independently selected from 1, 2, and 3; and-   other variables are as defined in Formula (III).

In another aspect, the present invention provides compounds of Formula(IVa):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvate, or prodrugs thereof,wherein:

-   R¹ is independently selected from: —CH₂OH, —OCH₃, —OCF₃, OCH₂Ph,    —C(═O)NR^(a)R^(a), —NR^(a)R^(a), CH₃, CH₂CH₃, CH(CH₃)₂, and    cyclopropyl;-   R² is independently selected from: C₁₋₄ alkyl substituted with 0-3    R^(e); C₂₋₄ alkenyl, C₃₋₆ cycloalkyl, and CH₂O(CH₂)₁₋₃CH₃;-   R³ is independently selected from:    -   (1) —(CR⁴R⁴)_(r)C(═O)OC₁₋₄ alkyl substituted with 0-3 R^(e),    -   (2) —(CR⁴R⁴)_(r)NR^(a)R^(a),    -   (3) —(CR⁴R⁴)_(r)C(═O)NR^(a)R^(a),    -   (4) —(CR⁴R⁴)_(r)NR^(a)C(═O)C₁₋₄alkyl substituted with 0-3 R^(e),    -   (5) —(CR⁴R⁴)_(r)NR^(a)C(═O)(CR⁴R⁴)_(n)OC₁₋₄alkyl substituted        with 0-3 R^(e),    -   (6) —(CR⁴R⁴)_(r)—R⁵,    -   (7) —(CR⁴R⁴)_(r)—OR⁵,    -   (8) —(CR⁴R⁴)_(r)NR^(a)C(═O)(CR⁴R⁴)_(n)R⁵, and    -   (9) —(CR⁴R⁴)_(r)C(═O)NR^(a)(CR⁴R⁴)_(n)R⁵;-   R⁴ is independently selected from: H, F, Cl, NR^(a)R^(a), OC₁₋₄    alkyl, and C₁₋₄ alkyl;-   R⁵ is independently selected from: aryl, C₃₋₆ cycloalkyl and    heterocycle, each substituted with 0-3 R⁶;-   R⁶ is independently selected from: H, F, Cl, Br, —OR^(b),    -   ═O, —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),        —(CH₂)_(n)NR^(a)R^(a), CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), C₁₋₄        alkyl substituted with 0-3 R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl        substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl        substituted with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5    -   R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a)        and R^(a) together with the nitrogen atom to which they are both        attached form a heterocyclic ring substituted with 0-5 R^(e);-   R^(b) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5    -   R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl (optionally    substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆    cycloalkyl, —(CH₂)_(n)—C₄₋₆    -   heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br,        CN, NO₂, ═O, CO₂H;-   n is independently selected from zero, 1, 2, and 3; and-   r is independently selected from 1, 2, and 3.

In another aspect, the present invention provides compounds of Formula(V):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvate, or prodrugs thereof,wherein:

-   R¹ is independently selected from: —CH₂OH, —OCH₃, —OCF₃, CH₃,    CH₂CH₃, CH(CH₃)₂, and cyclopropyl;-   R² is independently selected from: C₁₋₄ alkyl substituted with 0-3    R^(e); C₂₋₄ alkenyl, C₃₋₆ cycloalkyl, and CH₂O(CH₂)₁₋₃CH₃;-   R³ is independently selected from:    -   (1) —CH₂C(═O)OC₁₋₄ alkyl substituted with 0-3 R^(e),    -   (2) —CH₂NR^(a)R^(a),    -   (3) —CH₂C(═O)NR^(a)R^(a),    -   (4) —CH₂NHC(═O)C₁₋₄alkyl substituted with 0-3 R^(e),    -   (5) —CH₂NR^(a)C(═O)(CH₂)₀₋₂ C₁₋₄alkyl substituted with 0-3        R^(e),    -   (6) —CH₂—R⁵,    -   (7) —CH₂—OR⁵,    -   (8) —CH₂NR^(a)C(═O)(CH₂)₀₋₂R⁵, and    -   (9) —CH₂C(═O)NR^(a)(CH₂)₀₋₂R⁵;-   R⁵ is independently selected from: aryl, C₃₋₆ cycloalkyl and    heterocycle, each substituted with 0-3 R⁶;-   R⁶ is independently selected from: H, F, Cl, Br, —OR^(b),    -   ═O, —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),        —(CH₂)_(n)NR^(a)R^(a),    -   CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), —S(O)₂NH₂, C₁₋₄ alkyl        substituted with 0-3 R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl        substituted with 0-3 R^(e), and —(CH₂)_(n)-heterocyclyl        substituted with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5    -   R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a)        and R^(a) together with the nitrogen atom to which they are both        attached form a heterocyclic ring substituted with 0-5 R^(e);-   R^(b) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5    -   R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl (optionally    substituted with F and Cl),    -   OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆    -   heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br,        CN, NO₂, =O, CO₂H;-   n is independently selected from zero, 1, 2, and 3.

In another aspect, the present invention provides compounds of Formula(V), or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvate, or prodrugs thereof,wherein:

-   R³ is independently selected from:    -   (1) —CH₂—R⁵,    -   (2) —CH₂—OR⁵,    -   (3) —CH₂—NHC(═O)(CH₂)₀₋₁R⁵, and    -   (4) —CH₂—C(═O)NH(CH₂)₀₋₁R⁵;-   R⁵ is independently selected from:

-   R⁶ is independently selected from: H, F, Cl, Br, —OCH₃, —OCF₃, =O,    CN, CH₃, CF₃—(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted    with 0-3 R^(e),    -   and —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(6a) is independently selected from: H, CH₃, aryl substituted with    0-3 R^(e), and heterocyclyl substituted with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5    -   R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl (optionally    substituted with F and Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆    cycloalkyl, —(CH₂)_(n)—C₄₋₆    -   heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br,        CN, NO₂, =O, CO₂H;-   n is independently selected from zero, 1, 2, and 3.

In another aspect, the present invention provides compounds of Formula(VI):

or stereoisomers, enantiomers, diastereoisomers, tautomers,pharmaceutically acceptable salts, solvate, or prodrugs thereof,wherein:

-   R¹ is independently selected from: F, Cl, Br,    -   NO₂, —(CH₂)_(n)OR^(b), —(CH₂)_(n)C(═O)R^(b),        —(CH₂)_(n)NR^(a)R^(a), —(CH₂)_(n)C(═O)NR^(a)R^(a),        —(CH₂)_(n)NR^(a)C(═O)R^(b), C₁₋₄ alkyl substituted with 0-3        R^(e) and C₃₋₆ cycloalkyl substituted with 0-3 R^(e);-   R² is independently selected from: C₁₋₅ alkyl substituted with 0-3    R^(e); C₂₋₅ alkenyl, and C₃₋₆ cycloalkyl; wherein when R² is    independently selected from: C₁₋₅ alkyl, the carbon atom except the    one attached directly to the pyridine ring may be replaced by O, N,    and S;-   R³ is independently selected from:    -   (1) —CH₂C(═O)OC₁₋₄ alkyl substituted with 0-5 R^(e),    -   (2) —CH₂NR^(a)R^(a),    -   (3) —CH₂C(═O)NR^(a)R^(a),    -   (4) —CH₂NR^(a)C(═O)C₁₋₄alkyl substituted with 0-5 R^(e),    -   (5) —CH₂NR^(a)C(═O)(CH₂)_(n)OC₁₋₄alkyl substituted with 0-5        R^(e),    -   (6) —CH₂—R⁵,    -   (7) —CH₂—OR⁵,    -   (8) —CH₂NR^(a)C(═O)(CH₂)_(n)R⁵, and    -   (9) —CH₂C(═O)NR^(a)(CH₂)_(n)R⁵-   R⁵ is independently selected from: —(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆    cycloalkyl and —(CH₂)_(n)-heterocycle, each substituted with 0-3 R⁶;-   R⁶ is independently selected from: H, F, Cl, Br, —OR^(b),    -   ═O, —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b),        —(CH₂)_(n)NR^(a)R^(a),    -   CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), C₁₋₄ alkyl substituted with 0-3        R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e);-   R^(a) is independently selected from H, C₁₋₆ alkyl substituted with    0-5    -   R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a)        and R^(a) together with the nitrogen atom to which they are both        attached form a heterocyclic ring substituted with 0-5 R^(e);-   R^(b) is independently selected from H, C₁₋₆ alkyl substituted with    0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e), C₂₋₆ alkynyl    substituted with 0-5    -   R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e),        and —(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e);-   R^(e) is independently selected from C₁₋₆ alkyl substituted with 0-5    R_(f), C₂₋₆ alkenyl, C₂₋₆ alkynyl, —(CH₂)_(n)—C₃₋₆ cycloalkyl,    —(CH₂)_(n)—C₄₋₆    -   heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br,        CN, NO₂, =O, CO₂H, —(CH₂)_(n)OR_(f), S(O)_(p)R_(f),        C(═O)NR^(f)R^(f), NR^(f)C(═O)R^(f), S(O)_(p)NR^(f)R^(f),        NR^(f)S(O)_(p)R^(f), NR^(f)C(═O)OR^(f), OC(═O)NR^(f)R^(f) and        —(CH₂)_(n)NR^(f)R^(f);-   R^(f) is independently selected from H, F, Cl, Br, CN, OH, C₁₋₅alkyl    (optimally substituted with halogen and OH), C₃₋₆ cycloalkyl, and    phenyl;-   n is independently selected from zero, 1, 2, and 3; and-   p is independently selected from zero, 1, and 2.

In one non-limiting embodiment, ring A is

ring B is

R¹ is OC₁₋₄ alkyl; R² is independently selected from: C₁₋₅ alkylsubstituted with 0-3 R^(e); C₂₋₅ alkenyl, and C₃₋₆ cycloalkyl; providedwhen R² is C₁₋₅ alkyl, the carbon atom except the one attached directlyto the pyridine ring may be replaced by O, N, and S; R³ is CH₂—R⁵; R⁵ isaryl, C₃₋₆ cycloalkyl and heteroaryl, each substituted with 0-3 R⁶; R⁶is independently selected from: H, F, Cl, Br, —OR^(b), ═O,—(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)NR^(a)R^(a), CN,—(CH₂)_(n)C(═O)NR^(a)R^(a), —S(O)₂NH₂, C₁₋₄ alkyl substituted with 0-3R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R^(a) isindependently selected from H, C₁₋₆ alkyl substituted with 0-5 R^(e),—(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) and R^(a)together with the nitrogen atom to which they are both attached form aheterocyclic ring substituted with 0-5 R^(e); R^(b) is independentlyselected from H, C₁₋₆ alkyl substituted with 0-5 R^(e), C₂₋₆ alkenylsubstituted with 0-5 R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(e) isindependently selected from C₁₋₆ alkyl (optionally substituted with Fand Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl,—(CH₂)_(n)—C₄₋₆heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F,Cl, Br, CN, NO₂, =O, CO₂H; n is independently selected from zero, 1, 2,and 3.

In another non-limiting embodiment, ring A is

ring B is

R¹ is OC₁₋₄ alkyl; R² is independently selected from C₁₋₅ alkylsubstituted with 0-3 R^(e); and C₃₋₆ cycloalkyl; provided when R² isC₁₋₅ alkyl, the carbon atom except the one attached directly to thepyridine ring may be replaced by O; R³ is CH₂—R⁵; R⁵ is aryl, C₃₋₆cycloalkyl and heteroaryl, each substituted with 0-3 R⁶; R⁶ isindependently selected from: H, F, Cl, Br, —OR^(b),═O, —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)C(═O)OR^(b), —(CH₂)_(n)NR^(a)R^(a),CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), —S(O)₂NH₂, C₁₋₄ alkyl substituted with0-3 R^(e), (CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R^(a) isindependently selected from H, C₁₋₆ alkyl substituted with 0-5 R^(e),—(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); or R^(a) and R^(a)together with the nitrogen atom to which they are both attached form aheterocyclic ring substituted with 0-5 R^(e); R^(b) is independentlyselected from H, C₁₋₆ alkyl substituted with 0-5 R^(e), C₂₋₆ alkenylsubstituted with 0-5 R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),—(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(e) isindependently selected from C₁₋₆ alkyl (optionally substituted with Fand Cl), OH, OCH₃, OCF₃, —(CH₂)_(n)—C₃₋₆ cycloalkyl,—(CH₂)_(n)—C₄₋₆heterocyclyl, —(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F,Cl, Br, CN, NO₂, =O, CO₂H; n is independently selected from zero, 1, 2,and 3.

In another non-limiting embodiment, ring A is

ring B is

R¹ is OC₁₋₄ alkyl; R² is independently selected from: C₁₋₄ alkylsubstituted with 0-3 R^(e); C₂₋₄ alkenyl, C₃₋₆ cycloalkyl, andCH₂O(CH₂)₁₋₃CH₃; R³ is CH₂—R⁵; R⁵ is aryl or heteroaryl selected from

R⁶ is independently selected from: H, F, Cl, Br, —OCH₃, —OCF₃, =O, CN,CH₃, CF₃—(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with 0-3R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R^(6a) isindependently selected from: H, CH₃, R^(e) is independently selectedfrom C₁₋₆ alkyl (optionally substituted with F and Cl), OH, OCH₃, OCF₃,F, Cl, Br, CN, NO₂; n is independently selected from zero, 1, 2, and 3.

In another non-limiting embodiment, ring A is

ring B is

R¹ is OC₁₋₄ alkyl; R² is independently selected from: C₁₋₄ alkylsubstituted with 0-3 R^(e); C₂₋₄ alkenyl, C₃₋₆ cycloalkyl, andCH₂O(CH₂)₁₋₃CH₃; R³ is CH₂—R⁵; R⁵ is aryl or heteroaryl selected from

R⁶ is independently selected from: H, F, Cl, Br, —OCH₃, —OCF₃, =O, CN,CH₃, CF₃—(CH₂)_(n)-aryl, —(CH₂)_(n)—C₃₋₆ cycloalkyl substituted with 0-3R^(e), and —(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R^(6a) isindependently selected from: H, CH₃, R^(e) is independently selectedfrom C₁₋₆ alkyl (optionally substituted with F and Cl), OH, OCH₃, OCF₃,F, Cl, Br, CN, NO₂; n is independently selected from zero, 1, 2, and 3.

In another non-limiting embodiment, ring A is

ring B is

R¹ is OC₁₋₄ alkyl; R² is C₁₋₄ alkyl or CH₂O(CH₂)₁₋₃CH₃; R³ is CH₂—R⁵; R⁵is aryl or heteroaryl selected from

R⁶ is independently selected from: H, F, Cl, Br, —OCH₃, —OCF₃, CN, CH₃,and CF₃.

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This invention alsoencompasses all combinations of alternative aspects of the inventionnoted herein. It is understood that any and all embodiments of thepresent invention may be taken in conjunction with any other embodimentto describe additional embodiments of the present invention.Furthermore, any elements (including individual variable definitions) ofan embodiment are meant to be combined with any and all other elementsfrom any of the embodiments to describe additional embodiments. Thepresent invention also provides a pharmaceutical composition comprisinga compound of formula I, or an enantiomer, diastereomer, or apharmaceutically-acceptable salt, and a pharmaceutically acceptablecarrier therefore.

In another embodiment, the compounds of the present invention have EC₅₀values ≤10 μM, using the APJ hcAMP assay disclosed herein, preferably,EC₅₀ values ≤5 μM, more preferably, EC₅₀ values ≤1 μM, even morepreferably, EC₅₀ values ≤0.5 μM, even more preferably, EC₅₀ values ≤0.1μM, even more preferably, EC₅₀ values ≤0.01 μM.

In another aspect, the present invention provides compounds selectedfrom any subset list of compounds exemplified in the presentapplication.

In another aspect, the present invention provides compounds selectedfrom the subset in which the APJ hcAMP EC₅₀ potency range is A.

In another aspect, the present invention provides compounds selectedfrom the subset in which the APJ hcAMP EC₅₀ potency range is B.

In another aspect, the present invention provides compounds selectedfrom the subset in which the APJ hcAMP EC₅₀ potency range is C.

In another aspect, the present invention provides a compound selectedfrom

-   3-(5-benzyl-1,3,4-oxadiazol-2-yl)-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   3-(5-benzyl-1,3,4-oxadiazol-2-yl)-6-butyl-5-(2,6-dimethoxy-4-methylphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(pyridin-4-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(2-phenylethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   6-butyl-3-{5-[(2-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(2-methoxyphenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(3-methoxyphenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(4-methoxyphenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-3-[5-(3-chiorophenyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-3-[5-(2-chiorophenyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(pyrazin-2-yl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(1-phenylcyclopropyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   6-butyl-3-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(2-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(phenoxymethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   3-(5-benzyl-1,3,4-oxadiazol-2-yl)-6-(but-3-en-1-yl)-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(5-methyl-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(pyrazin-2-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(pyrimidin-5-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   6-butyl-3-{5-[(3-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-3-{5-[difluoro(phenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   3-[5-(1,3-benzoxazol-2-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-dimethoxy-4-methylphenyl)pyridine-2,4-diol,-   3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-(but-3-en-1-yl)-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[2-(5-phenyl-1,3-oxazol-2-yl)ethyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[2-(1-methyl-1H-imidazol-2-yl)ethyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-3-{5-[(6-chloropyridin-3-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-3-{5-[2-(4-chlorophenyl)propan-2-yl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(4-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-3-{5-[(3,4-dichlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[4-fluoro-3-(trifluoromethyl)phenyl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   6-butyl-3-{5-[(2,4-dichlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(3,5-dimethyl-1H-pyrazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   4-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)benzonitrile,-   6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-3-(5-{[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl}-1,3,4-oxadiazol-2-yl)-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-3-{5-[1-(4-chlorophenyl)ethyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(4-methyl-1,2,5-oxadiazol-3-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(4-fluorophenoxymethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(1H-indazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   4-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-1,2-dihydrophthalazin-1-one,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[methoxy(phenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(2-phenyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   3-{5-[2-(1,3-benzoxazol-2-yl)ethyl]-1,3,4-oxadiazol-2-yl}-6-butyl-5-(2,6-dimethoxyphenyl)pyri    dine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(4-fluoro-3-methoxyphenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(1,3-thiazol-5-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   6-butyl-3-[5-(3,4-dichlorophenoxymethyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(3-methyl-1,2-oxazol-5-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{2-[3-(pyrazin-2-yl)-1,2,4-oxadiazol-5-yl]ethyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   6-butyl-3-[5-(4-chlorophenoxymethyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-3-({5-[2-(4-chlorophenyl)-2-methylpropyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[4-(trifluoromethoxy)phenyl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[3-fluoro-5-(trifluoromethyl)phenyl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[2-(1-methyl-1H-1,3-benzodiazol-2-yl)ethyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-3-{5-[(2-chloropyridin-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{2-[3-(4-methoxyphenyl)-1,2,4-oxadiazol-5-yl]ethyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(1,2,3,4-tetrahydroisoquinolin-1-yl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   6-butyl-3-{5-[2-(3,4-dichlorophenyl)propan-2-yl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(2-methyl-2H-1,2,3,4-tetrazol-5-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(2-methyl-1-phenylpropan-2-yl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[4-(trifluoromethyl)phenoxymethyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(5-phenyl-4H-1,2,4-triazol-3-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-3-[5-(cyclohexylmethyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-3-{5-[2-(4-chlorophenyl)ethyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(oxan-4-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   6-butyl-3-{5-[(3-chloro-4-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-3-{5-[(4-chloro-3-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[2-(1,3-thiazol-2-yl)ethyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[3-(trifluoromethyl)phenyl]methyl}-1,3,4-oxadiazol-2-yl)pyri    dine-2,4-diol,-   6-butyl-3-{5-[2-(3,4-difluorophenyl)ethyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{2-[4-(trifluoromethyl)phenyl]ethyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   6-butyl-3-[5-(3,4-difluorophenoxymethyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[2-(3-phenyl-1,2,4-oxadiazol-5-yl)ethyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(1-phenyl-1H-pyrazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[4-(trifluoromethyl)phenyl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[2-(pyrimidin-2-yl)ethyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   3-{5-[2-(1,3-benzothiazol-2-yl)ethyl]-1,3,4-oxadiazol-2-yl}-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{2-[3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]ethyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(5-methyl-2-phenyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-3-{5-[2-(3,4-dichlorophenyl)ethyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-dichlorophenyl)pyridine-2,4-diol,-   6-butyl-3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dichlorophenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(dimethylamino)(4-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol,-   3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-cyclopropyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-6-cyclopropyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-cyclopropyl-5-(2,6-dimethoxyphenyl)-3-{5-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-cyclopropyl-5-(2,6-dimethoxyphenyl)-3-(5-{[3-(pyridin-2-yl)-1,2,4-oxadiazol-5-yl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   ethyl    2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}acetate,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(1,3-dimethyl-1H-pyrazol-5-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   3-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-1-methylimidazolidine-2,4-dione,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(3-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(piperidin-1-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[3-(pyridin-3-yl)-1,2,4-oxadiazol-5-yl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(1-methyl-1H-pyrazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-3-{5-[(4-chloro-2-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[3-(pyridin-4-yl)-1,2,4-oxadiazol-5-yl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   1-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)pyrrolidin-2-one,-   5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-(5-{[5-(pyridin-2-yl)-1,2,4-oxadiazol-3-yl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   3-{5-[(3-benzyl-1,2,4-oxadiazol-5-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-3-{5-[(3-cyclopropyl-1,2,4-oxadiazol-5-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   3-{5-[(6-chloropyridin-3-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(3-phenyl-1,2,4-oxadiazol-5-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   1-({5-[5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)pyrrolidin-2-one,-   3-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)imidazolidine-2,4-dione,-   1-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-1,2-dihydropyridin-2-one,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-[5-(1H-imidazol-1-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   3-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-1,3-oxazolidin-2-one,-   4-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)morpholin-3-one,-   tert-butyl    2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}acetate,-   1-({5-[5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-1,2-dihydropyridin-2-one,-   tert-butyl    N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)carbamate,-   tert-butyl    N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-N-methylcarbamate,-   3-{5-[(4-chloro-3-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol,-   3-{5-[(4-chloro-2-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol,-   5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(5-fluoropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-[5-(1H-imidazol-1-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(3-fluoro-4-methylphenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol,-   5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(3-phenyl-1H-pyrazol-1-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-(5-{[3-(trifluoromethyl)-1H-pyrazol-1-yl]methy}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(1-methyl-1H-pyrazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(6-fluoropyridin-3-yl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-[5-(1H-indazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   3-[5-(1H-1,2,3-benzotriazol-1-ylmethyl)-1,3,4-oxadiazol-2-yl]-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol,-   5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-[5-(1H-indazol-1-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(4-fluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-[5-(1H-indol-1-ylmethyl)-1,3,4-oxadiazol-2-yl]pyridine-2,4-diol,-   6-butyl-5-(3-ethylphenyl)-4-hydroxy-3-{5-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-1,2-dihydropyridin-2-one,-   3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-phenylpyridine-2,4-diol,-   6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3-methoxyphenyl)pyridine-2,4-diol,-   6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3-ethylphenyl)pyridine-2,4-diol,-   6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-[3-(trifluoromethoxy)phenyl]pyridine-2,4-diol,-   5-[3-(benzyloxy)phenyl]-6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-[3-(hydroxymethyl)phenyl]pyridine-2,4-diol,-   6-butyl-5-(cyclohex-1-en-1-yl)-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-[3-(propan-2-yl)phenyl]pyridine-2,4-diol,-   6-butyl-3-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-[3-(methoxymethyl)phenyl]pyridine-2,4-diol,-   3-(2-butyl-5-{5-[(3,4-difluorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-4,6-dihydroxypyridin-3-yl)-N-(propan-2-yl)benzamide,-   6-butyl-4-hydroxy-3-{5-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-[3-(propan-2-yl)phenyl]-1,2-dihydropyridin-2-one,-   3-(2-butyl-4-hydroxy-5-{5-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-oxo-1,6-dihydropyridin-3-yl)-N-(propan-2-yl)benzamide,-   6-butyl-5-(3-cyclopropylphenyl)-4-hydroxy-3-{5-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-1,2-dihydropyridin-2-one,-   6-butyl-4-hydroxy-5-(3-methoxyphenyl)-3-{5-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-1,2-dihydropyridin-2-one,-   6-butyl-4-hydroxy-5-[3-(hydroxymethyl)phenyl]-3-{5-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-1,2-dihydropyridin-2-one,-   6-butyl-4-hydroxy-3-{5-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-[3-(pyrrolidin-1-yl)phenyl]-1,2-dihydropyridin-2-one,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(methylamino)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-N-methyl-2-phenylacetamide,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-3-chloro-N-methylbenzamide,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-N-methylpyridine-2-carboxamide,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-2-methoxyacetamide,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-N-methylpyridine-4-carboxamide,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)pyridine-3-carboxamide,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-2-chloro-N-methylbenzamide,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-3-chlorobenzamide,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-4-chlorobenzamide,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)pyridine-4-carboxamide,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-N-methylpyridine-3-carboxamide,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-2-phenylacetamide,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-2,2-dimethylpropanamide,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)pyridine-2-carboxamide,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-N,2,2-trimethylpropanamide,-   3-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)benzamide,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-N-methylbenzamide,-   N-({5-[5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)benzamide,-   N—({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-3-methylbutanamide,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)acetamide,-   N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-2,2,2-trifluoroacetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N,N-diethylacetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(pyridin-2-ylmethyl)acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-methylacetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(propan-2-yl)acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N,N-dimethylacetamide,-   2-f{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(4-methoxyphenyl)acetamide,-   4-(2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}acetyl)piperazin-2-one,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-1-(4-methylpiperazin-1-yl)ethan-1-one,-   N-benzyl-2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-ethylacetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-cyclopropylacetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-propylacetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(2-fluoroethyl)acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(2,2-difluoroethyl)acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(2,2,2-trifluoroethyl)acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(2-methoxyethyl)acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-1-(pyrrolidin-1-yl)ethan-1-one,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-1-(piperidin-1-yl)ethan-1-one,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-1-(morpholin-4-yl)ethan-1-one,-   N-butyl-2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-pentylacetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-1-(3-fluoroazetidin-1-yl)ethan-1-one,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-1-(3,3-difluoroazetidin-1-yl)ethan-1-one,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(1,3-thiazol-2-yl)acetamide,-   3-(3-benzyl-1,2,4-oxadiazol-5-yl)-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadliazol-5-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   3-(5-benzyl-4H-1,2,4-triazol-3-yl)-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-3-(5-{[L-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3,4-oxadiazol-2-yl)-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[5-(pyridin-4-yl)-1,3,4-oxadiazol-2-yl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[5-(pyridin-2-yl)-1,3,4-oxadiazol-2-yl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   6-butyl-3-(5-{[5-(2-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3,4-oxadiazol-2-yl)-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   3-{5-[(5-benzyl-1,3,4-oxadiazol-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-3-(5-{[5-(3-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3,4-oxadiazol-2-yl)-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[5-(pyridin-3-yl)-1,3,4-oxadiazol-2-yl]methyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   1-({5-[6-(ethoxymethyl)-5-(4-fluoro-2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-1,2-dihydropyridin-2-one,-   3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-(ethoxymethyl)-5-(4-fluoro-2,6-dimethoxyphenyl)pyridine-2,4-diol,-   3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5-(4-fluoro-2,6-dimethoxyphenyl)pyridine-2,4-diol,-   1-({5-[6-(ethoxymethyl)-5-(4-fluoro-2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)pyrrolidin-2-one,-   3-{5-[(6-chloropyridin-3-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5-(4-fluoro-2,6-dimethoxyphenyl)pyridine-2,4-diol,-   3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadliazol-2-yl}-5-(3,5-dimethoxypyridin-4-yl)-6-(ethoxymethyl)pyridine-2,4-diol,-   6-butyl-3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3-fluoro-2,6-dimethoxyphenyl)pyridine-2,4-diol,-   3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(3-fluoro-2,6-dimethoxyphenyl)pyridine-2,4-diol,-   3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5-(2-hydroxy-6-methoxyphenyl)pyridine-2,4-diol,-   3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-dimethylphenyl)pyridine-2,4-diol,-   3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,4,6-trimethylphenyl)pyridine-2,4-diol,-   3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-diethylphenyl)pyridine-2,4-diol,-   6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[1,2]oxazolo[4,5-b]pyridin-3-ylmethyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-(5-{[1,2]oxazolo[4,5-b]pyridin-3-ylmethyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol,-   3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dihydroxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol,-   3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-[(ethylamino)methyl]pyridine-2,4-diol,-   3-{5-[(1,2-benzoxazol-3-yl)methyl]-1,3,4-thiadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol,-   3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-thiadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol,-   3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-thiadiazol-2-yl}-6-cyclopentyl-5-(2,6-dimethoxyphenyl)pyri    dine-2,4-diol,-   3-{5-[(4-chlorophenyl)methyl]-1,3,4-thiadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol,-   N-({5-[5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-thiadiazol-2-yl}methyl)pyridine-2-carboxamide,-   6-butyl-3-{5-[(5-chloro-3-fluoropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   3-{5-[(5-chloro-3-fluoropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol,-   3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-cyclopentyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-6-cyclopentyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol,-   3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-[(2-methoxyethoxy)methyl]pyridine-2,4-diol,-   3-{5-[(1,2-benzoxazol-3-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-[(2-methoxyethoxy)methyl]pyridine-2,4-diol,-   5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-3-{5-[(phenylamino)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol,-   3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-[(2-methoxyethoxy)methyl]pyridine-2,4-diol,-   N-({5-[6-butyl-5-(2,5-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)benzamide,-   N-[(5-{6-butyl-2,4-dihydroxy-5-[2-methoxy-5-(propan-2-yl)phenyl]pyridin-3-yl}-1,3,4-oxadiazol-2-yl)methyl]benzamide,-   3-{5-[(1,2-benzoxazol-3-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5-(2-methoxyphenyl)pyridine-2,4-diol,-   3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5-(2-methoxyphenyl)pyridine-2,4-diol,-   N-({5-[6-butyl-5-(2,3-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)benzamide,-   N-({5-[6-(ethoxymethyl)-2,4-dihydroxy-5-(2-methoxyphenyl)pyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)benzamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(pyridin-3-yl)acetamide,-   2-{5-[5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(1,3-thiazol-2-yl)acetamide,-   N-[(1,3-benzothiazol-2-yl)methyl]-2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[(pyridin-3-yl)methyl]acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[(1,3-oxazol-2-yl)methyl]acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[2-(4-sulfamoylphenyl)ethyl]acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[2-(2-chlorophenyl)ethyl]acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[(3-chlorophenyl)methyl]acetamide,-   N-benzyl-2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-methylacetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-methyl-N-(2-phenylethyl)acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(prop-2-yn-1-yl)acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-(3-methyl-1H-pyrazol-5-yl)acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[(2-methylphenyl)methyl]acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[(2-chlorophenyl)methyl]acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[(4-chlorophenyl)methyl]acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[2-(4-chlorophenyl)ethyl]acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[(pyridin-4-yl)methyl]acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[(4-methoxyphenyl)methyl]acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-{[4-(dimethylamino)phenyl]methyl}acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[(5-methyl-1,3,4-oxadiazol-2-yl)methyl]acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-{[3-(propan-2-yl)-1,2-oxazol-5-yl]methyl}acetamide,-   2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N-[(4-sulfamoylphenyl)methyl]acetamide,-   3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5-(2-hydroxy-6-methoxyphenyl)pyridine-2,4-diol,-   3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5-(2-hydroxy-6-methoxyphenyl)pyridine-2,4-diol,    and-   3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dihydroxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol,    or a stereoisomer, a tautomer, a pharmaceutically acceptable salt,    or a solvate thereof.

II. Other Embodiments of the Invention

In another embodiment, the present invention provides a compositioncomprising at least one of the compounds of the present invention or astereoisomer, a tautomer, a pharmaceutically acceptable salt, or asolvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition, comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, a tautomer, a pharmaceuticallyacceptable salt, or a solvate thereof.

In another embodiment, the present invention provides a process formaking a compound of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

In another embodiment, the present invention provides an intermediatefor making a compound of the present invention or a stereoisomer, atautomer, a pharmaceutically acceptable salt, or a solvate thereof.

The present invention provides a pharmaceutical composition furthercomprising additional therapeutic agent(s). In a preferred embodiment,the present invention provides pharmaceutical composition, wherein theadditional therapeutic agent is, for example, angiotensin convertingenzyme (ACE) inhibitor, β-adrenergic receptor blocker, angiotensin IIreceptor blocker, diuretic, aldosterone antagonist and digitaliscompound.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of multiple diseases or disordersassociated with APJ or apelin activity, comprising administering to apatient in need of such treatment and/or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone, or, optionally, in combination with another compoundof the present invention and/or at least one other type of therapeuticagent.

Examples of diseases or disorders associated with the activity of theAPJ and apelin that can be prevented, modulated, or treated according tothe present invention include, but are not limited to heart failure suchas acute decompensated heart failure (ADHF), atrial fibrillation,coronary artery disease, peripheral vascular disease, atherosclerosis,diabetes, metabolic syndrome, hypertension, pulmonary hypertension,cerebrovascular disorders and the sequelae thereof, cardiovasculardisorders, angina, ischemia, stroke, myocardial infarction, acutecoronary syndrome, reperfusion injury, angioplastic restenosis, vascularcomplications of diabetes and obesity.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of heart failure, coronary artery disease,peripheral vascular disease, atherosclerosis, diabetes, metabolicsyndrome, hypertension, pulmonary hypertension, atrial fibrillation,angina, ischemia, stroke, myocardial infarction, acute coronarysyndrome, reperfusion injury, angioplastic restenosis, vascularcomplications of diabetes, obesity, comprising administering to apatient in need of such treatment and/or prophylaxis a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone, or, optionally, in combination with another compoundof the present invention and/or at least one other type of therapeuticagent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of heart failure such as ADHF, comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention, alone, or, optionally, in combination withanother compound of the present invention and/or at least one other typeof therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of diabetes and obesity, comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention, alone, or, optionally, in combination withanother compound of the present invention and/or at least one other typeof therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of hypertension, comprising administeringto a patient in need of such treatment and/or prophylaxis atherapeutically effective amount of at least one of the compounds of thepresent invention, alone, or, optionally, in combination with anothercompound of the present invention and/or at least one other type oftherapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of pulmonary hypertension, comprisingadministering to a patient in need of such treatment and/or prophylaxisa therapeutically effective amount of at least one of the compounds ofthe present invention, alone, or, optionally, in combination withanother compound of the present invention and/or at least one other typeof therapeutic agent.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of acute coronary syndrome and cardiacischemia, comprising administering to a patient in need of suchtreatment and/or prophylaxis a therapeutically effective amount of atleast one of the compounds of the present invention, alone, or,optionally, in combination with another compound of the presentinvention and/or at least one other type of therapeutic agent.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy.

In another embodiment, the present invention provides a compound of thepresent invention for use in therapy for the treatment and/orprophylaxis of multiple diseases or disorders associated with APJ andapelin.

In another embodiment, the present invention also provides the use of acompound of the present invention for the manufacture of a medicamentfor the treatment and/or prophylaxis of multiple diseases or disordersassociated with APJ and apelin.

In another embodiment, the present invention provides a method for thetreatment and/or prophylaxis of multiple diseases or disordersassociated with APJ and apelin, comprising administering to a patient inneed thereof a therapeutically effective amount of a first and secondtherapeutic agent, wherein the first therapeutic agent is a compound ofthe present invention. Preferably, the second therapeutic agent, forexample selected inotropic agent such as β-adrenergic agonist (forexample dobutamine).

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use intherapy.

In another embodiment, the present invention provides a combinedpreparation of a compound of the present invention and additionaltherapeutic agent(s) for simultaneous, separate or sequential use in thetreatment and/or prophylaxis of multiple diseases or disordersassociated with APJ and apelin.

Where desired, the compound of the present invention may be used incombination with one or more other types of cardiovascular agents and/orone or more other types of therapeutic agents which may be administeredorally in the same dosage form, in a separate oral dosage form or byinjection. The other type of cardiovascular agents that may beoptionally employed in combination with the APJ agonist of the presentinvention may be one, two, three or more cardiovascular agentsadministered orally in the same dosage form, in a separate oral dosageform, or by injection to produce an additional pharmacological benefit.

The compounds of the present invention may be employed in combinationwith additional therapeutic agent(s) selected from one or more,preferably one to three, of the following therapeutic agents:anti-hypertensive agents, ACE inhibitors, mineralocorticoid receptorantagonists, angiotensin receptor blockers, calcium channel blockers,β-adrenergic receptor blockers, diuretics, vasorelaxation agents such asnitrates, anti-atherosclerotic agents, anti-dyslipidemic agents,anti-diabetic agents, anti-hyperglycemic agents, anti-hyperinsulinemicagents, anti-thrombotic agents, anti-retinopathic agents,anti-neuropathic agents, anti-nephropathic agents, anti-ischemic agents,calcium channel blockers, anti-obesity agents, anti-hyperlipidemicagents, anti-hypertriglyceridemic agents, anti-hypercholesterolemicagents, anti-restenotic agents, anti-pancreatic agents, lipid loweringagents, anorectic agents, memory enhancing agents, anti-dementia agents,cognition promoting agents, appetite suppressants, agents for treatingheart failure, agents for treating peripheral arterial disease, agentsfor treating malignant tumors, and anti-inflammatory agents.

In another embodiment, additional therapeutic agent(s) used in combinedpharmaceutical compositions or combined methods or combined uses, areselected from one or more, preferably one to three, of the followingtherapeutic agents in treating heart failure: ACE inhibitors,β-blockers, diuretics, mineralocorticoid receptor antagonists, renininhibitors, calcium channel blockers, angiotensin IIT receptorantagonists, nitrates, digitalis compounds, inotropic agents.

The present invention may be embodied in other specific forms withoutparting from the spirit or essential attributes thereof. This inventionencompasses all combinations of preferred aspects of the invention notedherein. It is understood that any and all embodiments of the presentinvention may be taken in conjunction with any other embodiment orembodiments to describe additional embodiments. It is also understoodthat each individual element of the embodiments is its own independentembodiment. Furthermore, any element of an embodiment is meant to becombined with any and all other elements from any embodiment to describean additional embodiment.

III. Chemistry

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo and optical isomers andracemates thereof where such isomers exist. Unless otherwise indicated,all chiral (enantiomeric and diastereomeric) and racemic forms arewithin the scope of the invention. Many geometric isomers of C═C doublebonds, C═N double bonds, ring systems, and the like can also be presentin the compounds, and all such stable isomers are contemplated in thepresent invention. Cis- and trans- (or E- and Z-) geometric isomers ofthe compounds of the present invention are described and may be isolatedas a mixture of isomers or as separated isomeric forms. The presentcompounds can be isolated in optically active or racemic forms.Optically active forms may be prepared by resolution of racemic forms orby synthesis from optically active starting materials. All processesused to prepare compounds of the present invention and intermediatesmade therein are considered to be part of the present invention. Whenenantiomeric or diastereomeric products are prepared, they may beseparated by conventional methods, for example, by chromatography orfractional crystallization. Depending on the process conditions the endproducts of the present invention are obtained either in free (neutral)or salt form. Both the free form and the salts of these end products arewithin the scope of the invention. If so desired, one form of a compoundmay be converted into another form. A free base or acid may be convertedinto a salt; a salt may be converted into the free compound or anothersalt; a mixture of isomeric compounds of the present invention may beseparated into the individual isomers. Compounds of the presentinvention, free form and salts thereof, may exist in multiple tautomericforms, in which hydrogen atoms are transposed to other parts of themolecules and the chemical bonds between the atoms of the molecules areconsequently rearranged. It should be understood that all tautomericforms, insofar as they may exist, are included within the invention.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For examples, “C₁ to C₁₂alkyl” or “C₁₋₁₂ alkyl” (or alkylene), is intended to include C₁, C₂,C₃, C₄, C₅, C₆, C₇, C₈, C₉, C₁₀, C₁₁ and C₁₂ alkyl groups; “C₄ to C₁₈alkyl” or “C₄₋₁₈ alkyl” (or alkylene), is intended to include C₄, C₅,C₆, C₇, C₈, C₉, C₁₀, C₁₁, C₁₂, C₁₃, C₁₄, C₁₅, C₁₆, C₁₇, and C₁₈ alkylgroups. Additionally, for example, “C₁ to C₆ alkyl” or “C₁₋₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Alkyl group can beunsubstituted or substituted with at least one hydrogen being replacedby another chemical group. Example alkyl groups include, but are notlimited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), and pentyl (e.g.,n-pentyl, isopentyl, neopentyl). When “C₀ alkyl” or

“C₀ alkylene” is used, it is intended to denote a direct bond.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having the specified number ofcarbon atoms and one or more, preferably one to two, carbon-carbondouble bonds that may occur in any stable point along the chain. Forexample, “C₂ to C₆ alkenyl” or “C₂₋₆ alkenyl” (or alkenylene), isintended to include C₂, C₃, C₄, C₅, and C₆ alkenyl groups. Examples ofalkenyl include, but are not limited to, ethenyl, 1-propenyl,2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3, pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and4-methyl-3-pentenyl.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration having one or more, preferablyone to three, carbon-carbon triple bonds that may occur in any stablepoint along the chain. For example, “C₂ to C₆ alkynyl” or “C₂₋₆ alkynyl”(or alkynylene), is intended to include C₂, C₃, C₄, C₅, and C₆ alkynylgroups; such as ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

When the term “hydrocarbon chain” is used, it is intended to include“alkyl”, “alkenyl” and “alkynyl”, unless otherwise specified.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group. Forexample, “C₁ to C₆ alkoxy” or “C₁₋₆ alkoxy” (or alkyloxy), is intendedto include C₁, C₂, C₃, C₄, C₅, and C₆ alkoxy groups. Example alkoxygroups include, but are not limited to, methoxy, ethoxy, propoxy (e.g.,n-propoxy and isopropoxy), and t-butoxy. Similarly, “alkylthio” or“thioalkoxy” represents an alkyl group as defined above with theindicated number of carbon atoms attached through a sulphur bridge; forexample methyl-S- and ethyl-S—.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogens. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” that is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁₋₆ haloalkoxy”, is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxyinclude, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly, “haloalkylthio”or “thiohaloalkoxy” represents a haloalkyl group as defined above withthe indicated number of carbon atoms attached through a sulphur bridge;for example trifluoromethyl-S-, and pentafluoroethyl-S—.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. For example, “C₃ to C₆ cycloalkyl” or“C₃₋₆ cycloalkyl” is intended to include C₃, C₄, C₅, and C₆ cycloalkylgroups. Example cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.Branched cycloalkyl groups such as 1-methylcyclopropyl and2-methylcyclopropyl are included in the definition of “cycloalkyl”. Theterm “cycloalkenyl” refers to cyclized alkenyl groups. C₄₋₆ cycloalkenylis intended to include C₄, C₅, and C₆ cycloalkenyl groups. Examplecycloalkenyl groups include, but are not limited to, cyclobutenyl,cyclopentenyl, and cyclohexenyl.

As used herein, “carbocycle”, “carbocyclyl”, or “carbocyclic residue” isintended to mean any stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclicor bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, or 13-membered bicyclic ortricyclic hydrocarbon ring, any of which may be saturated, partiallyunsaturated, unsaturated or aromatic. Examples of such carbocyclesinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl,cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl,cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl,[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shownabove, bridged rings are also included in the definition of carbocycle(e.g., [2.2.2]bicyclooctane). Preferred carbocycles, unless otherwisespecified, are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl,indanyl, and tetrahydronaphthyl. When the term “carbocycle” is used, itis intended to include “aryl.” A bridged ring occurs when one or more,preferably one to three, carbon atoms link two non-adjacent carbonatoms. Preferred bridges are one or two carbon atoms. It is noted that abridge always converts a monocyclic ring into a tricyclic ring. When aring is bridged, the substituents recited for the ring may also bepresent on the bridge.

As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclicgroup” is intended to mean a stable 9- or 10-membered carbocyclic ringsystem that contains two fused rings and consists of carbon atoms. Ofthe two fused rings, one ring is a benzo ring fused to a second ring;and the second ring is a 5- or 6-membered carbon ring which issaturated, partially unsaturated, or unsaturated. The bicycliccarbocyclic group may be attached to its pendant group at any carbonatom which results in a stable structure. The bicyclic carbocyclic groupdescribed herein may be substituted on any carbon if the resultingcompound is stable. Examples of a bicyclic carbocyclic group are, butnot limited to, naphthyl, 1,2-dihydronaphthyl,1,2,3,4-tetrahydronaphthyl, and indanyl.

“Aryl” groups refer to monocyclic or bicyclic aromatic hydrocarbons,including, for example, phenyl, and naphthyl. Aryl moieties are wellknown and described, for example, in Lewis, R. J., ed., Hawley'sCondensed Chemical Dictionary, 15th Edition, John Wiley & Sons, Inc.,New York (2007). “C₆₋₁₀ aryl” refers to phenyl and naphthyl.

The term “benzyl”, as used herein, refers to a methyl group on which oneof the hydrogen atoms is replaced by a phenyl group.

As used herein, the term “heterocycle”, “heterocyclyl”, or “heterocyclicgroup” is intended to mean a stable 3-, 4-, 5-, 6-, or 7-memberedmonocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-memberedpolycyclic heterocyclic ring that is saturated, partially unsaturated,or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4heteroatoms independently selected from the group consisting of N, O andS; and including any polycyclic group in which any of the above-definedheterocyclic rings is fused to a benzene ring. The nitrogen and sulfurheteroatoms may optionally be oxidized (i.e., N→O and S(O)_(p), whereinp is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted(i.e., N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and κ atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azetidinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzoxazolinyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolopyridinyl, oxazolidinylperimidinyl, oxindolyl,pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl,pyrazolyl, pyridazinyl, pyridooxazolyl, pyridoimidazolyl,pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrazolyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thiazolopyridinyl, thienothiazolyl, thienooxazolyl,thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Examples of 5- to 6-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “bicyclic heterocycle” or “bicyclicheterocyclic group” is intended to mean a stable 9- or 10-memberedheterocyclic ring system which contains two fused rings and consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, O and S. Of the two fused rings, one ring isa 5- or 6-membered monocyclic aromatic ring comprising a 5-memberedheteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, eachfused to a second ring. The second ring is a 5- or 6-membered monocyclicring which is saturated, partially unsaturated, or unsaturated, andcomprises a 5-membered heterocycle, a 6-membered heterocycle or acarbocycle (provided the first ring is not benzo when the second ring isa carbocycle).

The bicyclic heterocyclic group may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Thebicyclic heterocyclic group described herein may be substituted oncarbon or on a nitrogen atom if the resulting compound is stable. It ispreferred that when the total number of S and O atoms in the heterocycleexceeds 1, then these heteroatoms are not adjacent to one another. It ispreferred that the total number of S and O atoms in the heterocycle isnot more than 1.

Examples of a bicyclic heterocyclic group are, but not limited to,quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, indolyl,isoindolyl, indolinyl, 1H-indazolyl, benzimidazolyl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl,1,2,3,4-tetrahydro-quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted orunsubstituted. The nitrogen atom is substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). The nitrogenand sulfur heteroatoms may optionally be oxidized (i.e., N→O andS(O)_(p), wherein p is 0, 1 or 2).

Examples of 5- to 6-membered heteroaryls include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,imidazolyl, imidazolidinyl, tetrazolyl, isoxazolyl, oxazolyl,oxadiazolyl, oxazolidinyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl.

Bridged rings are also included in the definition of heterocycle. Abridged ring occurs when one or more, preferably one to three, atoms(i.e., C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.Examples of bridged rings include, but are not limited to, one carbonatom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and acarbon-nitrogen group. It is noted that a bridge always converts amonocyclic ring into a tricyclic ring. When a ring is bridged, thesubstituents recited for the ring may also be present on the bridge.

The term “counter ion” is used to represent a negatively charged speciessuch as chloride, bromide, hydroxide, acetate, and sulfate or apositively charged species such as sodium (Na+), potassium (K+),ammonium (R_(n)NH_(m)+ where n=0-4 and m=0-4) and the like.

When a dotted ring is used within a ring structure, this indicates thatthe ring structure may be saturated, partially saturated or unsaturated.

As used herein, the term “amine protecting group” means any group knownin the art of organic synthesis for the protection of amine groups whichis stable to an ester reducing agent, a disubstituted hydrazine, R4-Mand R7-M, a nucleophile, a hydrazine reducing agent, an activator, astrong base, a hindered amine base and a cyclizing agent. Such amineprotecting groups fitting these criteria include those listed in Wuts,P. G. M. et al., Protecting Groups in Organic Synthesis, 4th Edition,Wiley (2007) and The Peptides: Analysis, Synthesis, Biology, Vol. 3,Academic Press, New York (1981), the disclosure of which is herebyincorporated by reference. Examples of amine protecting groups include,but are not limited to, the following: (I) acyl types such as formyl,trifluoroacetyl, phthalyl, and p-toluenesulfonyl; (2) aromatic carbamatetypes such as benzyloxycarbonyl (Cbz) and substitutedbenzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and9-fluorenylmethyloxycarbonyl (Fmoc); (3) aliphatic carbamate types suchas tert-butyloxycarbonyl (Boc), ethoxycarbonyl,diisopropylmethoxycarbonyl, and allyloxycarbonyl; (4) cyclic alkylcarbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl;(5) alkyl types such as triphenylmethyl and benzyl; (6) trialkylsilanesuch as trimethylsilane; (7) thiol containing types such asphenylthiocarbonyl and dithiasuccinoyl; and (8) alkyl types such astriphenylmethyl, methyl, and benzyl; and substituted alkyl types such as2,2,2-trichloroethyl, 2-phenylethyl, and t-butyl; and trialkylsilanetypes such as trimethylsilane.

As referred to herein, the term “substituted” means that at least onehydrogen atom is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. Ring double bonds, as used herein, are double bondsthat are formed between two adjacent ring atoms (e.g., C═C, C═N, orN═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R, then said group mayoptionally be substituted with up to three R groups, and at eachoccurrence R is selected independently from the definition of R.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom in whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms that are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, and/or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound that contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Allen, Jr., L. V.,ed., Remington: The Science and Practice of Pharmacy, 22nd Edition,Pharmaceutical Press, London, UK (2012), the disclosure of which ishereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

-   a) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985), and    Widder, K. et al., eds., Methods in Enzymology, 112:309-396,    Academic Press (1985);-   b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”,    Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and    Development, pp. 113-191, Harwood Academic Publishers (1991);-   c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);-   d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988);-   e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984); and-   f) Rautio, J., ed., Prodrugs and Targeted Delivery (Methods and    Principles in Medicinal Chemistry), Vol. 47, Wiley-VCH (2011).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters that serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl (e.g., acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl),C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl (e.g., methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl), and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of prodrugs is well known in the art and described in, forexample, King, F. D., ed., Medicinal Chemistry: Principles and Practice,The Royal Society of Chemistry, Cambridge, UK (2nd Edition, reproduced(2006)); Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism.Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich,Switzerland (2003); Wermuth, C. G., ed., The Practice of MedicinalChemistry, 3rd Edition, Academic Press, San Diego, Calif. (2008).

The present invention is intended to include all isotopes of atomsoccurring in the present compounds. Isotopes include those atoms havingthe same atomic number but different mass numbers. By way of generalexample and without limitation, isotopes of hydrogen include deuteriumand tritium. Isotopes of carbon include ¹³C and ¹⁴C.Isotopically-labeled compounds of the invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described herein, using an appropriateisotopically-labeled reagent in place of the non-labeled reagentotherwise employed.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. The solvent molecules in the solvatemay be present in a regular arrangement and/or a non-orderedarrangement. The solvate may comprise either a stoichiometric ornonstoichiometric amount of the solvent molecules. “Solvate” encompassesboth solution-phase and isolable solvates. Exemplary solvates include,but are not limited to, hydrates, ethanolates, methanolates, andisopropanolates. Methods of solvation are generally known in the art.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or min, “h” forhour or h, “rt” for room temperature, “RT” for retention time, “atm” foratmosphere, “psi” for pounds per square inch, “conc.” for concentrate,“aq” for “aqueous”, “sat” or “sat'd” for saturated, “MW” for molecularweight, “mp” for melting point, “MS” or “Mass Spec” for massspectrometry, “ESI” for electrospray ionization mass spectroscopy, “HR”for high resolution, “HRMS” for high resolution mass spectrometry,“LCMS” for liquid chromatography mass spectrometry, “HPLC” for highpressure liquid chromatography, “RP HPLC” for reverse phase HPLC, “TLC”or “tlc” for thin layer chromatography, “NMR” for nuclear magneticresonance spectroscopy, “nOe” for nuclear Overhauser effectspectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet, “d” fordoublet, “t” for triplet, “q” for quartet, “m” for multiplet, “br” forbroad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, “Z” and “ee” arestereochemical designations familiar to one skilled in the art.

-   AcOH or HOAc acetic acid-   ACN acetonitrile-   Alk alkyl-   BBr₃ boron tribromide-   Bn benzyl-   Boc tert-butyloxycarbonyl-   BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium    hexafluorophosphate-   Bu butyl-   i-Bu isobutyl-   t-Bu tert-butyl-   t-BuOH tert-butanol-   Cbz carbobenzyloxy-   CDCl₃ deutero-chloroform-   CD₃OD deutero-methanol-   CDI 1,1′-carbonyldiimidazole-   CH₂Cl₂ dichloromethane-   CH₃CN acetonitrile-   CHCl₃ chloroform-   CO₂ carbon dioxide-   DCM dichloromethane-   DIEA, DIPEA or diisopropylethylamine Hunig's base-   DMF dimethyl formamide-   DMSO dimethyl sulfoxide-   EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide-   Et ethyl-   Et₃N or TEA triethylamine-   Et₂O diethyl ether-   EtOAc ethyl acetate-   EtOH ethanol-   HCl hydrochloric acid-   HPLC high-performance liquid chromatography-   K₂CO₃ potassium carbonate-   K₂HPO₄ potassium hydrogenphosphate-   LCMS liquid chromatography mass spectrometry-   LiHMDS lithium bis(trimethylsilyl)amide-   LG leaving group-   Me methyl-   MeOH methanol-   MgSO₄ magnesium sulfate-   MsOH or MSA methylsulfonic acid-   NaCl sodium chloride-   Na₂CO₃ sodium carbonate-   NaHCO₃ sodium bicarbonate-   NaOH sodium hydroxide-   Na₂SO₄ sodium sulfate-   NH₃ ammonia-   NH₄Cl ammonium chloride-   NH₄OAc ammonium acetate-   Pd(OAc)₂ palladium(II) acetate-   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(0)-   PG protecting group-   Ph phenyl-   Pr propyl-   i-Pr isopropyl-   i-PrOH or IPA isopropanol-   Rt retention time-   SiO₂ silica oxide-   SFC supercritical fluid chromatography-   TEA triethylamine-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TiCl₄ titanium tetrachloride-   T3P® 1-propanephosphonic acid cyclic anhydride

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. Restrictions to the substituents that are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

Synthesis

The compounds of Formula (I) may be prepared by the exemplary processesdescribed in the following schemes and working examples, as well asrelevant published literature procedures that are used by one skilled inthe art. Exemplary reagents and procedures for these reactions appearhereinafter and in the working examples. Protection and de-protection inthe processes below may be carried out by procedures generally known inthe art (see, for example, Wuts, P. G. M. et al., Protecting Groups inOrganic Synthesis, 4th Edition, Wiley (2007)). General methods oforganic synthesis and functional group transformations are found in:Trost, B. M. et al., eds., Comprehensive Organic Synthesis: Selectivity,Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, NewYork, N.Y. (1991); Smith, M. B. et al., March's Advanced OrganicChemistry. Reactions, Mechanisms, and Structure. 6th Edition, Wiley &Sons, New York, N.Y. (2007); Katritzky, A. R. et al, eds., ComprehensiveOrganic Functional Groups Transformations II, 2nd Edition, ElsevierScience Inc., Tarrytown, N.Y. (2004); Larock, R. C., ComprehensiveOrganic Transformations, VCH Publishers, Inc., New York, N.Y. (1999),and references therein.

Compounds of Formula (I) can be prepared as described in Scheme 1.

Step 1 describes the preparation of compounds of Formula G1b bycondensing an ester of Formula G1a with an acid R²CO-LG, where LGrepresents a leaving group (such as halogens and the like). Preferredsolvents are ethers (such as tetrahydrofuran, dioxane and the like) andpolar aprotic solvents (such as N,N-dimethylformamide). Preferred basesare metal amides (such as lithium bis(trimethylsilyl)amide and lithiumdiisopropylamide and the like) and metal hydrides (such as sodiumhydride and the like).

Step 2 describes the preparation of compounds of Formula G1c bycondensation of compounds of Formula G1b with ammonia. Preferred sourcesof ammonia are ammonia (gas) or salts thereof (such as ammonium acetate,ammonium formate and the like). Preferred solvents are alcohols (such asmethanol, ethanol and the like).

Step 3 describes the preparation of pyridine compounds of Formula G1dfrom compounds of formula G1c by condensation with malonate derivativesR^(b)OCOCH₂CO-LG, where LG represents a leaving group (such as halogensor alkoxides such as ethoxide and the like) in the presence of base. Theprocess can be performed in a single step, or stepwise. Preferredsolvents for the first step of the two step process are halogenatedsolvents (such as DCM and the like), ethers (such as tetrahydrofuran,dioxane and the like) and water. Preferred bases for the first step ofthe two step process are tertiary amines (such as TEA, DIEA and thelike) and alkaline metal-carbonates, -bicarbonates, -hydroxides (such assodium carbonate, sodium bicarbonate, sodium hydroxide and the like).Preferred solvents for the second step and for the single step processare alcohols (such as MeOH and EtOH and the like). Preferred bases forthe second step and for the single step process are alkaline metalalkoxides (such as sodium ethoxide and the like).

Step 4 describes the preparation of compounds of Formula (I) byconversion of the ester of compounds of Formula G1d to a heterocycle{circle around (A)}. The conversion of compounds of Formula G1d tocompounds of Formula (I) can be performed in one step or in severalsteps, depending on the heterocycle {circle around (A)}. The ester ofFormula G1 d can be condensed neat with an N′-hydroxy imidamide to givea 1,2,4-oxadiazole in a single step. Alternatively in a two step processthe ester of Formula G1d can by condensed with hydrazine in the presenceof alcohol solvents (such as methanol and the like) to form a hydrazide,then the hydrazide condensed with an acid in the presence of adehydrating reagents (such as T3P®, EDC and the like) and an inertsolvent (such as dioxane, EtOAc and the like) to give a1,3,4-oxadiazole. Alternatively, the hydrazide can be condensed with animidate in alcohol solvents (such as isopropanol and the like) in thepresence of tertiary amines (such as TEA, DIEA and the like) to give a1,3,4-triazole.

Alternatively compounds of Formula (I) can be prepared as described inScheme 2.

Step 1 describes the preparation of compounds of Formula G2b from acompound of Formula G2a (prepared as described in W2007/197478), whereLG represents a leaving group (such as halogens, preferably bromine).Preferred reagents for incorporating the leaving group are sources ofbromine (such as elemental bromine and NBS and the like). Preferredsolvents are halogenated solvents (such as DCM and the like).

Step 2 describes the preparation of a compound of Formula G2c from acompound of Formula G2b and is analogous to Step 4 in Scheme 1.

Step 3 describes the prepartion of compounds of Formula (I) by couplingan organometallic reagent M-(alk)₀₋₂-{circle around (B)}—(R¹)₁₋₄ with acompound of Formula G2c. The organometallic reagent M-(alk)₀₋₂-{circlearound (B)}—(R¹)₁₋₄ is preferably generated by reaction of aalkylboronic acid or ester B(OR)₂-(alk)₀₋₂-{circle around (B)}—(R¹)₁₋₄,R═H or alkyl, with a transition metal catalyst (such as Pd(PPh₃)₄ andPd(OAc)₂ and the like). Preferred solvents are ethers (such astetrahydrofuran, dioxane and the like), aprotic solvents (such astoluene and the like) and water. Preferred bases are alkalinemetal-carbonates, -bicarbonates (such as sodium carbonate, sodiumbicarbonate and the like).

Alternatively compounds of Formula (I) can be prepared as described inScheme 3.

Step 1 describes the preparation of compounds of Formula G3b bybromination of an ester of Formula G3a. Preferred sources of bromine areelemental bromine and NBS and the like. Preferred solvents are ethers(such as tetrahydrofuran, dioxane and the like). Preferred bases aremetal amides (such as lithium bis(trimethylsilyl)amide and lithiumdiisopropylamide and the like) and metal hydrides (such as sodiumhydride and the like).

Step 2 describes the preparation of compounds of Formula G3c fromcompounds of Formula G3b via condensation with nitrile R²—CN in thepresence of a transition metal. The preferred transition metal is zinc,and a co-catylst (zinc oxide, alkyl sulfonic acids and the like) can beused. Inert solvents such as ethers (such as tetrahydrofuran, dioxaneand the like) and aprotic solvents (such as toluene and the like) can beused, preferably the reaction is run under neat conditions.

Step 3 describes the preparation of a compound of Formula G3d from acompound of Formula G2c and is analogous to Step 3 in Scheme 1.

Step 3 describes the preparation of a compound of Formula (I) from acompound of Formula G3d and is analogous to Step 4 in Scheme 1.

IV. Biology

APJ receptor was discovered in 1993 as an orphan G protein-coupledreceptor (GPCR) and was subsequently found to recognize apelin peptideas its endogenous ligand. It belongs to class A of GPCRs and has aclassical 7-transmembrane domain structure, exhibiting greatest sequencehomology to angiotensin AT1 receptor (for review see Pitkin, S. L. etal., Pharmacol. Rev., 62(3):331-342 (2010)). APJ is expressed in widevariety of peripheral tissues and the CNS, and has relatively highexpression in placenta, myocardium, vascular endothelial cells, smoothmuscle cells as well as cardiac myocytes (Kleinz, J. M. et al.,Pharmacol. Ther., 107(2):198-211(2005)). Apelin peptide was originallyidentified in bovine stomach extract and remains to date the only knownendogenous ligand and agonist of APJ receptor (Tatemoto, K. et al.,Biochem. Biophys. Res. Commun., 255:471-476 (1998)). Tissue expressionof apelin gene mirrors closely the APJ expression pattern and has beenpostulated to act in an autocrine or paracrine manner, often exemplifiedby reference to “apelin-APJ system”. Apelin gene encodes 77 amino acidprecursor peptide that is cleaved to form mature secreted peptideundergoing further proteolytic cleavage forming shorter C-terminalfragments. Apelin-36, -17 and -13 represent the major active forms withthe pyroglutamated form of apelin-13 being the most stable and the mostabundant form present in the cardiac tissue (Maguire, J. J. et al.,Hypertension, 54(3):598-604 (2009)). Apelin has very short half life incirculation, estimated to be less than 5 minutes (Japp, A. G. et al.,Circulation, 121(16):1818-1827 (2010)).

Activation of APJ receptor is known to inhibit forskolin-stimulatedcyclic AMP (cAMP) levels in pertussis toxin-sensitive manner, indicatingcoupling to the Gi proteins. The binding affinity of apelin and the EC₅₀values in the cAMP assay are reported to be in the sub-nanomolar range(for review see Pitkin, S. L. et al., Pharmacol. Rev.,62(3):331-342(2010)). In addition to cAMP inhibition, APJ receptoractivation also leads to β-arrestin recruitment, receptorinternalization and activation of extracellular-regulated kinases (ERKs)(for review see Kleinz, J. M. et al., Pharmacol. Ther., 107(2):198-211(2005)). Which of these signaling mechanisms contribute to modulation ofdownstream physiological effects of apelin is not clear at present. APJreceptor has been shown to interact with the AT1 receptor. While apelindoes not bind AT1 and angiotensin 11 does not bind APJ, it has beenpostulated that certain physiological actions of apelin are mediated, atleast in part, via functional antagonism of the angiotensin II and AT1receptor pathway (Chun, A. J. et al., J. Clin. Invest.,118(10):3343-3354 (2008)).

It is also desirable and preferable to find compounds with advantageousand improved characteristics compared with known HF treatment agents, inone or more of the following categories that are given as examples, andare not intended to be limiting: (a) pharmacokinetic properties,including oral bioavailability, half life, and clearance; (b)pharmaceutical properties; (c) dosage requirements; (d) factors thatdecrease blood drug concentration peak-to-trough characteristics; (e)factors that increase the concentration of active drug at the receptor;(f) factors that decrease the liability for clinical drug-druginteractions; (g) factors that decrease the potential for adverseside-effects, including selectivity versus other biological targets; and(h) improved therapeutic index.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, the term “subject” refers to any human or non-humanorganism that could potentially benefit from treatment with an APJagonist. Exemplary subjects include human beings of any age with riskfactors for development of heart failure and the sequelae thereof,angina, ischemia, cardiac ischemia, myocardial infarction, reperfusioninjury, angioplastic restenosis, hypertension, vascular complications ofdiabetes, obesity or endotoxemia, stroke, as well as atherosclerosis,coronary artery disease, acute coronary syndrome, and/or dyslipidemias.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)inhibiting the disease-state, i.e., arresting it development; and/or (b)relieving the disease-state, i.e., causing regression of the diseasestate.

As used herein, “prophylaxis” or “prevention” cover the preventivetreatment of a subclinical disease-state in a mammal, particularly in ahuman, aimed at reducing the probability of the occurrence of a clinicaldisease-state. Patients are selected for preventative therapy based onfactors that are known to increase risk of suffering a clinical diseasestate compared to the general population. “Prophylaxis” therapies can bedivided into (a) primary prevention and (b) secondary prevention.Primary prevention is defined as treatment in a subject that has not yetpresented with a clinical disease state, whereas secondary prevention isdefined as preventing a second occurrence of the same or similarclinical disease state.

As used herein, “risk reduction” covers therapies that lower theincidence of development of a clinical disease state. As such, primaryand secondary prevention therapies are examples of risk reduction.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to modulate APJ and/or to prevent or treat thedisorders listed herein. When applied to a combination, the term refersto combined amounts of the active ingredients that result in thepreventive or therapeutic effect, whether administered in combination,serially, or simultaneously.

A. Assay Methods

Intracellular cAMP Accumulation Assay

HEK293 cells stably expressing human APJ receptor were used to assessthe activity of compounds. Cultured cells were detached and resuspendedin the cAMP Homogeneous Time-Resolved Fluorescence (HTRF) assay buffer(Cisbio cat; #62AM4PEJ). The assay was performed in 384-well assayplates (Perkin-Elmer; cat #6008289) according to assay protocol providedby the manufacturer. Serial dilutions of a compound together with assaybuffer containing 0.2 nM IBMX and 2 μM forskolin were added to each wellcontaining 5,000 cells and incubated for 30 minutes at room temperature.Subsequently, cAMP D2 reagent was added in the lysis buffer followed bythe EuK antibody (Cisbio; cat #62AM4PEJ) and incubated for 60 min. Thefluorescence emission ratio was measured using fluorometer. Theintracellular cAMP concentrations (compound-stimulated inhibition offorskolin-mediated cAMP production) were calculated by extrapolationfrom a standard curve using known cAMP concentrations. The EC₅₀ valueswere obtained by fitting the data to a sigmoidal concentration-responsecurve with variable slope. The maximal achievable inhibition offorskolin-induced cAMP levels (Y_(max)) for each compound was expressedas relative percentage of inhibition attained using pyroglutamatedapelin-13 ((Pyr1)apelin-13) peptide, which was set to 100%.

The examples disclosed below were tested in the APJ in vitro assaysdescribed above and were found having human APJ cyclic AMP (hcAMP)activity. The EC₅₀ value of each compound is presented at the end of theexample description.

The compounds of the present invention possess activity as agonists ofAPJ receptor, and, therefore, may be used in the treatment of diseasesassociated with APJ activity. Accordingly, the compounds of the presentinvention can be administered to mammals, preferably humans, for thetreatment of a variety of conditions and disorders, including, but notlimited to, treating, preventing, or slowing the progression of heartfailure, coronary artery disease, peripheral vascular disease,atherosclerosis, diabetes, metabolic syndrome and the sequelae ofthereof, hypertension, pulmonary hypertension, cerebrovasculardisorders, atrial fibrillation, angina, ischemia, stroke, myocardialinfarction, acute coronary syndrome, reperfusion injury, angioplasticrestenosis, vascular complications of diabetes and obesity.

The biological activity of the exemplified compounds of this inventiondetermined by the assay described above is shown at the end of eachexample. The APJ cAMP EC₅₀ potency ranges are as follows: A=0.01-10 nM;B=10.01-100 nM; C=100.01-300 nM.

V. Pharmaceutical Compositions, Formulations and Combinations

The compounds of this invention can be administered for any of the usesdescribed herein by any suitable means, for example, orally, such astablets, capsules (each of which includes sustained release or timedrelease formulations), pills, powders, granules, elixirs, tinctures,suspensions (including nanosuspensions, microsuspensions, spray-drieddispersions), syrups, and emulsions; sublingually; bucally;parenterally, such as by subcutaneous, intravenous, intramuscular, orintrasternal injection, or infusion techniques (e.g., as sterileinjectable aqueous or non-aqueous solutions or suspensions); nasally,including administration to the nasal membranes, such as by inhalationspray; topically, such as in the form of a cream or ointment; orrectally such as in the form of suppositories. They can be administeredalone, but generally will be administered with a pharmaceutical carrierselected on the basis of the chosen route of administration and standardpharmaceutical practice.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.

Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Allen, Jr., L. V. et al., Remington: The Science andPractice of Pharmacy (2 Volumes), 22nd Edition, Pharmaceutical Press(2012),

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to about 5000 mg per day, preferably between about 0.01 toabout 1000 mg per day, and most preferably between about 0.1 to about250 mg per day. Intravenously, the most preferred doses will range fromabout 0.01 to about 10 mg/kg/minute during a constant rate infusion.Compounds of this invention may be administered in a single daily dose,or the total daily dosage may be administered in divided doses of two,three, or four times daily.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, e.g., oral tablets, capsules,elixirs, and syrups, and consistent with conventional pharmaceuticalpractices.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 2000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

A typical capsule for oral administration contains at least one of thecompounds of the present invention (250 mg), lactose (75 mg), andmagnesium stearate (15 mg). The mixture is passed through a 60 meshsieve and packed into a No. 1 gelatin capsule.

A typical injectable preparation is produced by aseptically placing atleast one of the compounds of the present invention (250 mg) into avial, aseptically freeze-drying and sealing. For use, the contents ofthe vial are mixed with 2 mL of physiological saline, to produce aninjectable preparation.

The present invention includes within its scope pharmaceuticalcompositions comprising, as an active ingredient, a therapeuticallyeffective amount of at least one of the compounds of the presentinvention, alone or in combination with a pharmaceutical carrier.Optionally, compounds of the present invention can be used alone, incombination with other compounds of the invention, or in combinationwith one or more other therapeutic agent(s), e.g., agents used intreatment of heart failure or other pharmaceutically active material.

The compounds of the present invention may be employed in combinationwith other APJ agonists or one or more other suitable therapeutic agentsuseful in the treatment of the aforementioned disorders including:agents for treating heart failure, anti-hypertensive agents,anti-atherosclerotic agents, anti-dyslipidemic agents, anti-diabeticagents, anti-hyperglycemic agents, anti-hyperinsulinemic agents,anti-thrombotic agents, anti-retinopathic agents, anti-neuropathicagents, anti-nephropathic agents, anti-ischemic agents, anti-obesityagents, anti-hyperlipidemic agents, anti-hypertriglyceridemic agents,anti-hypercholesterolemic agents, anti-restenotic agents,anti-pancreatic agents, lipid lowering agents, anorectic agents, memoryenhancing agents, anti-dementia agents, cognition promoting agents,appetite suppressants, and agents for treating peripheral arterialdisease.

The compounds of the present invention may be employed in combinationwith additional therapeutic agent(s) selected from one or more,preferably one to three, of the following therapeutic agents in treatingheart failure and coronary artery disease: ACE inhibitors, β-blockers,diuretics, mineralocorticoid receptor antagonists, renin inhibitors,calcium channel blockers, angiotensin II receptor antagonists, nitrates,digitalis compounds, inotropic agents and β-receptor agonists,anti-hyperlipidemic agents, plasma HDL-raising agents,anti-hypercholesterolemic agents, cholesterol biosynthesis inhibitors(such as HMG CoA reductase inhibitors), LXR agonist, probucol,raloxifene, nicotinic acid, niacinamide, cholesterol absorptioninhibitors, bile acid sequestrants (such as anion exchange resins, orquaternary amines (e.g., cholestyramine or colestipol), low densitylipoprotein receptor inducers, clofibrate, fenofibrate, benzofibrate,cipofibrate, gemfibrizol, vitamin B₆, vitamin B₁₂, anti-oxidantvitamins, anti-diabetes agents, platelet aggregation inhibitors,fibrinogen receptor antagonists, aspirin and fibric acid derivatives.

The compounds of the invention may be used in combination with one ormore, preferably one to three, of the following anti-diabetic agentsdepending on the desired target therapy. Studies indicate that diabetesand hyperlipidemia modulation can be further improved by the addition ofa second agent to the therapeutic regimen. Examples of anti-diabeticagents include, but are not limited to, sulfonylureas (such aschlorpropamide, tolbutamide, acetohexamide, tolazamide, glyburide,gliclazide, glynase, glimepiride, and glipizide), biguanides (such asmetformin), thiazolidinediones (such as ciglitazone, pioglitazone,troglitazone, and rosiglitazone), and related insulin sensitizers, suchas selective and non-selective activators of PPARα, PPARPβ and PPARγ;dehydroepiandrosterone (also referred to as DHEA or its conjugatedsulphate ester, DHEA-SO₄); anti-glucocorticoids; TNFα inhibitors;dipeptidyl peptidase IV (DPP4) inhibitor (such as sitagliptin,saxagliptin), GLP-1 agonists or analogs (such as exenatide),α-glucosidase inhibitors (such as acarbose, miglitol, and voglibose),pramlintide (a synthetic analog of the human hormone amylin), otherinsulin secretagogues (such as repaglinide, gliquidone, andnateglinide), insulin, as well as the therapeutic agents discussed abovefor treating heart failure and atherosclerosis.

The compounds of the invention may be used in combination with one ormore, preferably one to three, of the following anti-obesity agentsselected from phenylpropanolamine, phentermine, diethylpropion,mazindol, fenfluramine, dexfenfluramine, phentiramine, β₃-adrenergicreceptor agonist agents; sibutramine, gastrointestinal lipase inhibitors(such as orlistat), and leptins. Other agents used in treating obesityor obesity-related disorders include neuropeptide Y, enterostatin,cholecytokinin, bombesin, amylin, histamine H₃ receptors, dopamine D₂receptor modulators, melanocyte stimulating hormone, corticotrophinreleasing factor, galanin and gamma amino butyric acid (GABA).

The above other therapeutic agents, when employed in combination withthe compounds of the present invention may be used, for example, inthose amounts indicated in the Physicians' Desk Reference, as in thepatents set out above, or as otherwise determined by one of ordinaryskill in the art.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients but also to control the release of one of these componentsin the gastrointestinal tract such that one of these components is notreleased in the stomach but rather is released in the intestines. One ofthe active ingredients may also be coated with a material that affects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a low viscosity grade ofhydroxypropyl methylcellulose (HPMC) or other appropriate materials asknown in the art, in order to further separate the active components.The polymer coating serves to form an additional barrier to interactionwith the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. By“administered in combination” or “combination therapy” it is meant thatthe compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination, each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the APJ receptor and apelin activity. Suchcompounds may be provided in a commercial kit, for example, for use inpharmaceutical research involving APJ and apelin or anti-heart failureactivity. For example, a compound of the present invention could be usedas a reference in an assay to compare its known activity to a compoundwith an unknown activity. This would ensure the experimenter that theassay was being performed properly and provide a basis for comparison,especially if the test compound was a derivative of the referencecompound. When developing new assays or protocols, compounds accordingto the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving APJ and apelin.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises a first therapeutic agent, comprising a compound of thepresent invention or a pharmaceutically acceptable salt form thereof;and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment and/or prophylaxis of multiple diseases ordisorders associated with APJ and apelin (as defined previously). Inanother embodiment, the package insert states that the pharmaceuticalcomposition can be used in combination (as defined previously) with asecond therapeutic agent for the treatment and/or prophylaxis ofmultiple diseases or disorders associated with APJ and apelin. Thearticle of manufacture can further comprise: (d) a second container,wherein components (a) and (b) are located within the second containerand component (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

VI. Examples

The following Examples are offered as illustrative, as a partial scopeand particular embodiments of the invention and are not meant to belimiting of the scope of the invention. Abbreviations and chemicalsymbols have their usual and customary meanings unless otherwiseindicated. Unless otherwise indicated, the compounds described hereinhave been prepared, isolated and characterized using the schemes andother methods disclosed herein or may be prepared using the same.

As a person of ordinary skill in the art would be able to understandthat a pyridone in a molecule may tautomerize to its keto and enol formsas shown in the following equation, wherein R¹, R², R³ and R⁴ are asdefined above, this disclosure is intended to cover all possibletautomers even when a structure depicts only one of them.

Description of Analytical LCMS Methods:

Method A: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 mparticles; Mobile Phase A: 5:95 ACN:water with 10 mM NH₄OAc; MobilePhase B: 95:5 ACN:water with 10 mM NH₄OAc; Temperature: 50° C.;Gradient: 0-100% B over 3 minutes, then a 0.75 minute hold at 100% B;Flow: 1.11 mL/min; Detection: UV at 220 nm.

Method B: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 mparticles; Mobilie Phase A: 5:95 ACN:water with 0.1% TFA; Mobile PhaseB: 95:5 ACN:water with 0.1% TFA; Temperature: 50° C.; Gradient: 0-100% Bover 3 minutes, then a 0.75 minute hold at 100% B; Flow: 1.11 mL/min;Detection: UV at 220 nm.

Method C: Column: PHENOMENEX® Luna 3 μm C18 (2.0×30 mm); Mobilie PhaseA: 10:90 MeOH:water with 0.1% TFA; Mobile Phase B: 90:10 MeOH:water with0.1% TFA; Gradient: 0-100% B over 2 minutes, then a 1 minute hold at100% B; Flow: 1 mL/min; Detection: UV at 220 nm.

Method D: Column: Waters Acquity UPLC BEH C18, 2.1×50 mm, 1.7 mparticles; Mobilie Phase A: water with 0.1% TFA; Mobile Phase B: ACNwith 0.1% TFA; Gradient: 2-98% B over 1 minute, then a 0.5 minute holdat 98% B; Flow: 0.8 mL/min; Detection: UV at 220 nm.

Method E: Column: Phenomenex Luna 3u C18(2) 2.0×30 mm; Mobile Phase A:10:90 MeOH:water with 10 mM NH₄OAc; Mobile Phase B: 90:10 MeOH:waterwith 10 mM NH₄OAc; Gradient: 0-100% B over 2 minute, then a 1 minutehold at 100% B; Temperature: 40° C.; Flow: 1.00 mL/min; Detection: UV at220 nm.

Example 1.3-(5-benzyl-1,3,4-oxadiazol-2-yl)-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol

Compound 1a. Ethyl 2-(2,6-dimethoxyphenyl)acetate

To a solution of 1,3-dimethoxybenzene (3.3 mL, 25 mmol) in THF (40 mL)was added dropwise 2.5M nBuLi in hexanes (10 mL, 25 mmol) over a 10 minperiod then the mixture stirred for 2 h. Crushed copper(I) iodide (2.38g, 12.5 mmol) was added slowly then the mixture stirred for 1 h, turninghomogeneous. The mixture was cooled to −78° C. then ethyl bromoacetate(2.8 mL, 25 mmol) was added dropwise over 20 min. The cold bath wasremoved and the mixture allowed to warm to room temperature. The mixturewas quenched by the addition of water then Et₂O added and the mixturefiltered through celite. The filtrate was diluted with 1.5N K₂HPO₄ andextracted with Et₂O (2×). The extracts were washed with brine, dried(MgSO₄) filtered and concentrated under reduced pressure. The residuewas purified by silica gel chromatography eluting with 0 to 15%EtOAc/hexanes to give Compound 1a (4.8 g, 86% yield) as a light brownoil which solidified upon standing. MS m/z=225.1 (M+H). ¹H NMR (500 MHz,CDCl₃) δ 7.23 (t, J=8.4 Hz, 1H), 6.58 (d, J=8.3 Hz, 2H), 4.17 (q, J=7.2Hz, 2H), 3.83 (s, 6H), 3.71 (s, 2H), 1.27 (t, J=7.2 Hz, 3H).

Compound 1b. Ethyl 2-(2,6-dimethoxyphenyl)-3-hydroxyhept-2-enoate

To a solution of Compound 1a (1.50 g, 6.70 mmol) in THF (14 mL) at −78°C. was added dropwise 1.0M LiHMDS in THF (16.7 mL, 16.7 mmol) and themixture was stirred for 10 min then at room temperature for 1 h. Themixture was cooled to −78° C. then valeryl chloride (1.34 mL, 11.0 mmol)was added dropwise and the mixture allowed to warm to 0° C. and stirredfor 15 min. The mixture was quenched with satd NH₄Cl and extracted withEtOAc (3×). The combined extracts were washed with brine, dried (Na₂SO₄)filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with 0 to 30%EtOAc/hexanes to give an isomeric mixture of Compound 1b (1.81 g, 88%yield) as a clear colorless oil. MS m/z=309.1 (M+H). ¹H NMR of majorisomer (400 MHz, CDCl₃) δ 13.22 (s, 1H), 7.26-7.22 (m, 1H), 6.56 (d,J=8.6 Hz, 2H), 4.14 (q, J=7.0 Hz, 2H), 3.75 (s, 5H), 2.05-1.96 (m, 2H),1.51-1.42 (m, 2H), 1.22-1.17 (m, 2H), 1.14 (t, J=7.2 Hz, 3H), 0.77 (t,J=7.3 Hz, 3H).

Compound 1c. Ethyl 3-amino-2-(2,6-dimethoxyphenyl)hept-2-enoate

To the isomeric mixture of Compound 1b (1.8 g, 5.9 mmol) and ammoniumformate (1.9 g, 29 mmol) in absolute ethanol (35 mL) was added molecularsieves then the mixture heated at reflux for 10 h. The mixture wasallowed to cool to room temperature then filtered and concentrated underreduced pressure. The residue was dissolved in water and extracted withEtOAc (3×). The combined extracts were dried (Na₂SO₄) filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 0 to 35% EtOAc/hexanes to give Compound1c (1.2 g, 68% yield) as a clear colorless oil. MS m/z=308.1 (M+H). ¹HNMR (400 MHz, CDCl₃) δ 7.21 (t, J=8.4 Hz, 1H), 6.55 (d, J=8.4 Hz, 2H),4.05 (q, J=7.0 Hz, 2H), 3.75 (s, 6H), 1.98-1.88 (m, 2H), 1.43-1.31 (m,2H), 1.18 (dt, J=15.0, 7.5 Hz, 2H), 1.09 (t, J=7.0 Hz, 3H), 0.73 (t,J=7.4 Hz, 3H).

Compound 1d. Ethyl6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxynicotinate

To a solution of Compound 1c (1.23 g, 4.00 mmol) in a mixture of DCM (20mL) and 1N NaHCO₃(24 mL, 24 mmol) was added dropwise a solution of ethylmalonyl chloride (1.54 mL, 12.0 mmol) in DCM (5 mL) and the mixturevigorously stirred for 10 min. The mixture was diluted with DCM, thelayers separated, and aqueous layer extracted with DCM (2×). Thecombined extracts were washed with satd NH₄Cl and brine, dried (Na₂SO₄)filtered and concentrated under reduced pressure. The residue wasdissolved in absolute EtOH (20 mL) then 2.5M sodium ethoxide in ethanol(6.4 mL, 16 mmol) added and the mixture stirred for 24 h, generating aprecipitate. The mixture was evaporated to dryness then diluted withsatd NH₄Cl and extracted with DCM (3×). The combined extracts werewashed with brine, dried (Na₂SO₄), decanted and concentrated underreduced pressure onto celite. The residue was purified by silica gelchromatography eluting with 5 to 75% EtOAc/DCM to give Compound 1d (0.52g, 35% yield) as a white solid. MS m/z=376.1 (M+H). ¹H NMR (400 MHz,DMSO-d₆) δ 7.33 (t, J=8.4 Hz, 1H), 6.70 (d, J=8.4 Hz, 2H), 4.30 (q,J=6.8 Hz, 2H), 3.68 (s, 6H), 2.09 (t, J=7.2 Hz, 2H), 1.37-1.23 (m, 5H),1.12-0.99 (m, 2H), 0.65 (t, J=7.4 Hz, 3H).

Compound 1e.6-Butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxynicotinohydrazide

To a suspension of Compound 1d (50 mg, 0.13 mmol) in ethanol (0.75 mL)was added hydrazine (0.084 mL, 2.6 mmol) and the mixture stirred for 0.5h. The mixture was concentrated under reduced pressure to give Compound1e (47 mg, 98% yield) as a white solid. MS m/z=362.1 (M+H). ¹H NMR (400MHz, DMSO-d₆) δ 15.52 (s, 1H), 11.78 (br. s., 1H), 10.89 (t, J=4.4 Hz,1H), 7.34 (t, J=8.4 Hz, 1H), 6.71 (d, J=8.4 Hz, 2H), 4.72 (d, J=4.8 Hz,2H), 3.68 (s, 6H), 2.18-2.09 (m, 2H), 1.32 (quin, J=7.5 Hz, 2H),1.14-1.02 (m, 2H), 0.66 (t, J=7.4 Hz, 3H).

Example 1.3-(5-benzyl-1,3,4-oxadiazol-2-yl)-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol

To a solution of Compound 1e (15 mg, 0.042 mmol) in dioxane (0.4 mL) wasadded phenylacetic acid (6.2 mg, 0.046 mmol) followed by a 50% solutionof T3P® in ethyl acetate (0.075 mL, 0.13 mmol) and the mixture heated bymicrowave irradiation at 160° C. for 1 h. The mixture was concentratedunder reduced pressure then purified by prep HPLC to give Example 1 (14mg, 72% yield). LCMS (Method A) Rt=1.83 min, m/z=462.1 (M+H). ¹H NMR(500 MHz, DMSO-d₆) δ 7.42-7.23 (m, 6H), 6.73 (d, J=8.2 Hz, 2H), 4.36 (s,2H), 3.68 (s, 6H), 2.15 (t, J=7.3 Hz, 2H), 1.39-1.27 (m, 2H), 1.14-1.02(m, 2H), 0.70-0.60 (m, 3H). Human APJ cAMP EC₅₀ Potency range B.

Example 2 to Example 136 were prepared as described in the generalprocedure given for Example 1.

Example 137.6-butyl-5-(3-ethylphenyl)-4-hydroxy-3-{5-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-1,2-dihydropyridin-2-one

Compound 137b. Ethyl 5-bromo-6-butyl-2,4-dihydroxynicotinate

Bromine (0.55 mL, 11 mmol) was added to Compound 137a (1.7 g, 7.1 mmol;prepared as described in W2007/197478) in DCM (40 mL). After 15 minutes,the reaction mixture was concentrated and purified by silica gelchromatography eluting with 0 to 5% methanol/DCM to give Compound 137b(2.2 g, 99% yield) as a white solid. LCMS (Method D) Rt=0.90 min,m/z=320.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 14.28 (s, 1H), 12.09-11.75(m, 1H), 4.45 (q, J=7.0 Hz, 2H), 2.95-2.71 (m, 2H), 1.80-1.64 (m, 2H),1.52-1.37 (m, 5H), 0.98 (t, J=7.4 Hz, 3H).

Compound 137c. 5-Bromo-6-butyl-2,4-dihydroxynicotinohydrazide

Hydrazine (0.77 mL, 25 mmol) was added to Compound 137b (750 mg, 2.47mmol) in MeOH (20 mL). After 16 hours, the reaction mixture wasconcentrated under reduced pressure, suspended in methanol (10 mL), andthe solid collected via Buchner filtration to give Compound 137c (690mg, 92% yield) as a white solid. LCMS (Method D) Rt=0.74 min, m/z=305.9[M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 3.30 (s, 2H), 2.58 (br. s., 2H),1.53 (d, J=7.4 Hz, 2H), 1.39-1.26 (m, 2H), 0.89 (t, J=7.4 Hz, 3H).

Compound 137d.5-Bromo-6-butyl-3-(5-((2-methylthiazol-4-yl)methyl)-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol

Compound 137d (190 mg, 45% yield) was prepared from Compound 137c asdescribed for Example 1. LCMS (Method D) Rt=0.87, m/z=426.9 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 12.09-11.87 (m, 1H), 7.43 (s, 1H), 4.43 (s,2H), 2.72-2.64 (m, 2H), 2.62 (s, 3H), 1.62-1.51 (m, 2H), 1.40-1.30 (m,2H), 0.91 (t, J=7.3 Hz, 3H).

Example 137.6-butyl-5-(3-ethylphenyl)-4-hydroxy-3-{5-[(2-methyl-1,3-thiazol-4-yl)methyl]-1,3,4-oxadiazol-2-yl}-1,2-dihydropyridin-2-one

Compound 137d (15 mg, 0.035 mmol), (3-ethylphenyl)boronic acid (7.9 mg,0.053 mmol) and Pd(PPh₃)₄ (12.2 mg, 10.6 μmol) in dioxane (1 mL)/2MNa₂CO₃ (0.5 mL) were purged with argon and then heated at 100° C. After2 hours, the reaction mixture was filtered, concentrated, dissolved inDMF/methanol and purified by prep HPLC to give Example 137 (3.2 mg, 20%yield). LCMS (Method A) Rt=1.88 min, n/z=451.0. ¹H NMR (500 MHz,DMSO-d₆) δ 7.42 (s, 1H), 7.38-7.28 (m, 1H), 7.21 (d, J=7.3 Hz, 1H),7.14-6.99 (m, 2H), 4.43 (s, 2H), 2.72-2.58 (m, 5H), 2.28 (br. s., 2H),1.50-1.34 (m, 2H), 1.26-1.14 (m, 3H), 1.15-1.01 (m, 2H), 0.67 (t, J=7.3Hz, 3H). Human APJ cAMP EC₅₀ Potency range B.

Example 138 to Example 153 were prepared as described in the generalprocedure given for Example 137.

Example 154 and Example 155.6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(methylamino)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diolandN-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-N-methyl-2-phenylacetamide

Example 154.6-butyl-5-(2,6-dimethoxyphenyl)-3-{5-[(methylamino)methyl]-1,3,4-oxadiazol-2-yl}pyridine-2,4-diol

To a solution of Example 121 (450 mg, 0.88 mmol) in DCM (3 mL) was addedTFA (3 mL) and the mixture was stirred at rt for 30 min. The reactionmixture was concentrated under reduced pressure to give Example 154 (330mg, 88% yield). LCMS (Method C) Rt=1.59 min, m/z=415.1 (M+H). ¹H NMR(500 MHz, DMSO-d₆) δ 7.37 (t, J=8.4 Hz, 1H), 6.75 (d, J=8.5 Hz, 2H),4.06 (s, 2H), 3.71 (s, 6H), 2.45-2.36 (m, 3H), 2.17 (t, J=7.4 Hz, 2H),1.39-1.28 (m, 2H), 1.16-1.04 (m, 2H), 0.68 (t, J=7.2 Hz, 3H). Human APJcAMP EC₅₀ Potency range B.

Example 155.N-({5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-N-methyl-2-phenylacetamide

To a solution of Example 154 (12 mg, 0.029 mmol) and 2-phenylacetic acid(4.7 mg, 0.035 mmol) in DMF (0.5 mL) was added BOP reagent (15 mg, 0.035mmol) followed by triethylamine (0.020 mL, 0.15 mmol) and the mixturestirred for 1 h. The reaction mixture was concentrated under reducedpressure then purified by prep HPLC to give Example 155 (13 mg, 83%yield). LCMS (Method C) Rt=2.07 min, m/z=533.2 (M+H). ¹H NMR (500 MHz,DMSO-d₆) δ 7.43-7.16 (m, 6H), 6.80-6.68 (m, 2H), 4.88 (s, 2H), 3.82 (s,2H), 3.70 (s, 6H), 2.52 (br. s., 3H), 2.20-2.11 (m, 2H), 1.41-1.28 (m,2H), 1.18-1.02 (m, 2H), 0.67 (t, J=7.3 Hz, 3H). Human APJ cAMP EC₅₀Potency range A.

Example 156 to Example 176 were prepared as described in the generalprocedure given for Example 155.

Example 177.2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N,N-diethylacetamide

Example 177.2-{5-[6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}-N,N-diethylacetamide

To a solution of Example 118 (122 mg, 0.250 mmol) in DCM (2 mL) wasadded TFA (2 mL) and the reaction mixture was stirred at rt for 30 min.The reaction mixture was concentrated under reduced pressure to give theintermediate acid (120 mg, 90% yield). To a portion of the intermediateacid (10 mg, 0.023 mmol) in DMF (0.5 mL) was added diethylamine (0.003mL, 0.05 mmol) followed by BOP reagent (12 mg, 0.028 mmol) andtriethylamine (0.016 mL, 0.12 mmol) and the mixture stirred for 1 h. Themixture was concentrated under reduced pressure then purified by prepHPLC to give Example 177 (4.0 mg, 34% yield). LCMS (Method C) Rt=1.90min, m/z=485.1 (M+H). ¹H NMR (500 MHz, DMSO-d₆) δ 7.37 (t, J=8.3 Hz,1H), 6.74 (d, J=8.5 Hz, 2H), 4.27 (s, 2H), 3.70 (s, 6H), 2.56 (s, 6H),2.17 (t, J=7.7 Hz, 2H), 1.34 (t, J=7.8 Hz, 2H), 1.20 (t, J=7.0 Hz, 2H),1.12-1.03 (m, 4H), 0.67 (t, J=7.3 Hz, 3H). Human APJ cAMP EC₅₀ Potencyrange A.

Example 178 to Example 201 were prepared as described in the generalprocedure given for Example 177.

Example 202.3-(3-benzyl-1,2,4-oxadiazol-5-yl)-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol

Example 202.3-(3-benzyl-1,2,4-oxadiazol-5-yl)-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol

A vial containing Compound 1d (25 mg, 0.067 mmol) andN′-hydroxy-2-phenylacetimidamide (50 mg, 0.33 mmol) was sealed thenstirred at 120° C. for 3 h. The reaction mixture was purified by prepHPLC to give Example 202 (8.0 mg, 26% yield). LCMS (Method C) Rt=2.17min, m/z=462.1 (M+H). ¹H NMR (500 MHz, DMSO-d₆) δ 7.48-7.32 (m, 5H),7.31-7.23 (m, 1H), 6.73 (d, J=8.5 Hz, 2H), 4.15 (s, 2H), 3.68 (s, 6H),2.17 (t, J=7.7 Hz, 2H), 1.34 (t, J=7.7 Hz, 2H), 1.15-1.02 (m, 2H), 0.67(t, J=7.3 Hz, 3H). Human APJ cAMP EC₅₀ Potency range B.

Example 203 was prepared as described in the general procedure given forExample 202.

Example 204.3-(5-benzyl-4H-1,2,4-triazol-3-yl)-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol

Example 204.3-(5-benzyl-4H-1,2,4-triazol-3-yl)-6-butyl-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol

To a solution of Compound 1e (6.0 mg, 0.017 mmol) and ethyl2-phenylacetimidate (2.7 mg, 0.017 mmol) in 2-propanol (0.3 mL) wasadded DIEA (0.10 mL, 0.57 mmol) and the reaction mixture heated at 120°C. using microwave irradiation for 20 min. The reaction mixture wasconcentrated under reduced pressure then purified by prep HPLC to giveExample 204 (5.3 mg, 56% yield). LCMS (Method C) Rt=2.21 min, m/z=461.2(M+H). ¹H NMR (500 MHz, DMSO-d₆) 7.34 (t, J=8.4 Hz, 1H), 7.30-7.26 (m,4H), 7.23-7.17 (m, 1H), 6.71 (d, J=8.6 Hz, 2H), 4.02 (s, 2H), 3.73-3.59(m, 6H), 2.20-2.07 (m, 2H), 1.33 (dt, J=15.3, 7.5 Hz, 2H), 1.08 (s×t,J=7.4 Hz, 2H), 0.66 (t, J=7.4 Hz, 3H). Human APJ cAMP EC₅₀ Potency rangeC.

Example 205.6-butyl-3-(5-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3,4-oxadiazol-2-yl)-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol

Example 205.6-butyl-3-(5-{[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]methyl}-1,3,4-oxadiazol-2-yl)-5-(2,6-dimethoxyphenyl)pyridine-2,4-diol

To a solution of Example 96 (500 mg, 1.1 mmol) in ethanol (5 mL) wasadded hydrazine (0.35 mL, 11 mmol) and the mixture stirred for 1 h. Themixture was concentrated under reduced pressure to give the intermediatehydrazide (480 mg, 98% yield) as a white solid. MS m/z=441.1 (M+H). Aportion of the intermediate hydrazide (20 mg, 0.045 mmol) and4-chlorobenzoic acid (8.5 mg, 0.054 mmol) were dissolved in dioxane (1mL) then DIEA (0.020 mL, 0.11 mmol) added followed by a 50% solution ofT3P® in ethyl acetate (0.067 mL, 0.11 mmol) and the mixture heated at60° C. for 1 h. To the reaction mixture additional DIEA (0.020 mL, 0.11mmol) and 50% solution of T3P® in ethyl acetate (0.067 mL, 0.11 mmol)were added and the reaction mixture was heated at 90° C. for 16 h. Thereaction mixture was concentrated under reduced pressure then purifiedby prep HPLC to give Example 205 (9.7 mg, 38% yield). LCMS (Method D)Rt=0.97 min, m/z=564.3 (M+H). ¹H NMR (500 MHz, DMSO-d₆) δ 8.03 (d, J=8.3Hz, 2H), 7.70 (d, J=8.3 Hz, 2H), 7.35 (t, J=8.5 Hz, 1H), 6.73 (d, J=8.5Hz, 2H), 4.96 (s, 2H), 3.70 (s, 6H), 2.14 (t, J=7.6 Hz, 2H), 1.41-1.26(m, 2H), 1.16-1.01 (m, 2H), 0.67 (t, J=7.3 Hz, 3H). Human APJ cAMP EC₅₀Potency range B.

Example 206 to Example 211 were prepared as described in the generalprocedure given for Example 205.

Example 212.1-({5-[6-(ethoxymethyl)-5-(4-fluoro-2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-1,2-dihydropyridin-2-one

Compound 212a. 4-Fluoro-2,6-dimethoxybenzaldehyde

To a stirred solution of 1-fluoro-3,5-dimethoxybenzene (3.00 g, 19.2mmol) in DCM (45 mL) was slowly added a 1.0 M solution of TiCl₄ in DCM(38.4 mL, 38.4 mmol) at 0° C. over 15 min. The reaction mixture wascooled to −78° C. and treated with dichloro(methoxy)methane (2.26 mL,25.0 mmol) dropwise. The reaction mixture was stirred at −78° C. for 30min and allowed to warm to 0° C. After 1 hour, the reaction mixture waspoured into dilute HCl and extracted with ethyl acetate (2×). Thecombined organic fractions were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified on silicagel chromatography eluting with 0% to 30% ACN/DCM to afford Compound212a (1.60 g, 45%) as a white solid. MS m/z=184.9 (M+H). ¹H NMR (400MHz, CDCl₃) δ 10.42 (s, 1H), 6.34 (s, 1H), 6.31 (s, 1H), 3.91 (s, 6H)

Compound 212b. (4-Fluoro-2,6-dimethoxyphenyl)methanol

To a suspension of Compound 212a (2.52 g, 13.7 mmol) in ethanol (60 mL)at 0° C. was added sodium borohydride (0.35 g, 9.1 mmol). The ice bathwas removed and stirring continued for 20 min. The reaction mixture wascooled to 0° C. then quenched by the addition of sat'd ammonium chloridesolution. The resulting suspension was concentrated and redissolved inEtOAc/water mixture. The layers were separated and the organic fractionwas washed with brine, dried over Na₂SO₄, and concentrated under reducedpressure to give Compound 212b (2.3 g, 90%) as a white solid which wasused without further purification. LCMS (Method C) Rt=1.38 min. ¹H NMR(400 MHz, CDCl₃) δ 6.33 (s, 1H), 6.31 (s, 1H), 4.74 (m, 2H), 3.85 (s,6H)

Compound 212c. 4-Fluoro-2,6-dimethoxybenzyl methanesulfonate

To a solution of Compound 212b (2.3 g, 13 mmol) in DCM (80 mL) was addedTEA (3.5 mL, 25 mmol). The reaction mixture was cooled to 0° C. andtreated with mesyl chloride (7.4 mL, 0.095 mol) in DCM (25 mL). After 30min, the reaction mixture was diluted with DCM (100 mL) and washed withwater (3×50 mL). The organic layer was dried over Na₂SO₄ andconcentrated under reduced pressure to give Compound 212c (2.7 g, 82%)which was used without further purification. LCMS (Method C) Rt=1.64min. ¹H NMR (400 MHz, CDCl₃) δ 6.23 (s, 1H), 6.20 (s, 1H), 4.64 (s, 2H),3.78 (s, 6H)

Compound 212d. 2-(4-Fluoro-2,6-dimethoxyphenyl)acetonitrile

To a solution of Compound 212c (2.7 g, 10 mmol) in DMF (40 mL) was addedsodium cyanide (1.0 g, 20 mmol) and the reaction mixture was stirred for30 min. The reaction mixture was diluted with water (800 mL) andextracted with 30% ethyl acetate in hexane (3×200 mL). The combinedorganic layers were dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by silica gel chromatography elutingwith 0 to 5% ethyl acetate in hexane to give Compound 212d (1.8 g, 88%).MS m/z=196.0 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 6.67 (s, 1H), 6.64 (s,1H), 3.85 (s, 6H), 3.65 (s, 2H)

Compound 212e. Ethyl 2-(4-fluoro-2,6-dimethoxyphenyl)acetate

To a solution of Compound 212d (1.75 g, 8.97 mmol) in EtOH (40 mL) wasbubbled HCl gas for 2 h. The reaction mixture was concentrated underreduced pressure and the residue was diluted with water (50 mL) andheated at 40° C. overnight. After allowing to cool to rt, the reactionmixture was extracted with ethyl acetate (3×50 mL). The combined organiclayers were dried over Na₂SO₄ and concentrated under reduced pressure togive Compound 212e (1.6 g, 76%). MS m/z=243.1 (M+H). ¹H NMR (400 MHz,DMSO-d₆) δ 6.58 (s, 1H), 6.55 (s, 1H), 4.05 (q, J=7.0 Hz, 2H), 3.76 (s,6H), 3.49 (s, 2H), 1.17 (t, J=7.2 Hz, 3H)

Example 212.1-({5-[6-(ethoxymethyl)-5-(4-fluoro-2,6-dimethoxyphenyl)-2,4-dihydroxypyridin-3-yl]-1,3,4-oxadiazol-2-yl}methyl)-1,2-dihydropyridin-2-one

Example 212 was prepared from Compound 212e as described in the generalprocedure for Example 1 in 5% yield. LCMS (Method C) Rt=1.66 min,m/z=499.1 (M+H). ¹H NMR (400 MHz, CDCl₃) δ 7.51 (m, 1H), 7.46 (m, 1H),6.72 (d, J=9.0 Hz, 1H), 6.42 (s, 1H), 6.40 (s, 1H), 6.38-6.33 (m, 1H),5.49 (s, 2H), 4.19 (s, 2H), 3.75 (s, 6H), 3.57 (m, 2H), 1.28 (t, J=6.9Hz, 3H). Human APJ cAMP EC₅₀ Potency range B.

Example 213 to Example 216 were prepared as described in the generalprocedure given for Example 212.

Example 217.3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3,5-dimethoxypyridin-4-yl)-6-(ethoxymethyl)pyridine-2,4-diol

Compound 217a. (3,5-Dimethoxypyridin-4-yl)methanol

To a suspension of 3,5-dimethoxyisonicotinaldehyde (300 mg, 1.80 mmol)in ethanol (12 mL) at 0° C. was added sodium borohydride (45.2 mg, 1.20mmol). The ice bath was removed and stirring continued for 20 min. Thereaction mixture was cooled to 0° C. and quenched by addition of sat'dammonium chloride. The resulting suspension was concentrated andredissolved in EtOAc/water. The reaction mixture was extracted withEtOAc and the organic extracts washed with brine, dried over MgSO₄, andconcentrated to give Compound 217a (0.30 g, 98%) as a clear oil. MSm/z=170.0 (M+H). ¹H NMR (400 MHz, CDCl₃) δ 8.04 (s, 2H), 4.77 (s, 2H),3.95 (s, 6H)

Compound 217b. 2-(3,5-Dimethoxypyridin-4-yl)acetonitrile

To a solution of Compound 217a (400 mg, 2.3 mmol) in DCM (14 mL) and TEA(0.49 mL, 3.6 mmol) at 0° C. was added dropwise a solution of mesylchloride (7.4 mL, 0.095 mol) in DCM (25 mL). After 0.5 h the mixture wasdiluted with DCM (100 mL) and washed with water (3×50 mL). The organiclayer was dried over Na₂SO₄ and concentrated under reduced pressure toafford a light brown oil which was dissolved in DMF (10 mL) and treatedwith sodium cyanide (0.23 g, 4.7 mmol). The reaction mixture was stirredfor 0.5 h then diluted with water (80 mL) and extracted with 30% ethylacetate in hexane (3×200 mL). The combined organic extracts were driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with 0-65% ethyl acetatein hexane to give Compound 217b (200 mg, 47%) as a white solid. MSm/z=179.0 (M+H).

Compound 217c. Ethyl 2-(3,5-dimethoxypyridin-4-yl)acetate

To a solution of Compound 217b (200 mg, 1.12 mmol) in EtOH (8 mL) wasbubbled HCl gas for 2 h. The reaction mixture was concentrated underreduced pressure and the residue was diluted with water (15 mL) andheated at 40° C. for 14 h. After allowing to cool to rt, the reactionmixture was extracted with ethyl acetate (3×50 mL). The combined organiclayers were dried over magnesium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by silica gelchromatography eluting with 0-100% ethyl acetate in hexane to giveCompound 217c (220 mg, 87%) as a clear oil. MS m/z=226.0 (M+H). ¹H NMR(400 MHz, CDCl₃) δ 8.02 (br. s., 2H), 4.15 (q, J=7.1 Hz, 2H), 3.91 (s,6H), 3.67 (s, 2H), 1.24 (t, J=7.0 Hz, 3H)

Example 217.3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3,5-dimethoxypyridin-4-yl)-6-(ethoxymethyl)pyridine-2,4-diol

Example 217 was prepared from Compound 217c as described in the generalprocedure for Example 1 in 1% yield. LCMS (Method C) Rt=1.67 min,m/z=499.0 (M+H). ¹H NMR (400 MHz, CDCl₃) δ 8.16 (s, 2H), 7.33 (m, 4H),4.30 (s, 2H), 4.12 (s, 2H), 3.89 (s, 6H), 3.53 (m, 2H), 1.25 (t, J=7.0Hz, 31-H). Human APJ cAMP EC₅₀ Potency range B.

Example 218.6-butyl-3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3-fluoro-2,6-dimethoxyphenyl)pyridine-2,4-diol(isomer 1) and Example 219.6-butyl-3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3-fluoro-2,6-dimethoxyphenyl)pyridine-2,4-diol(isomer 2)

Compound 218a. Ethyl6-butyl-5-(3-fluoro-2,6-dimethoxyphenyl)-2,4-dihydroxynicotinate

To a solution of Compound 1d (650 mg, 1.73 mmol) in DMF (7.5 mL) at 0°C. was slowly added Selectfluor™ (613 mg, 1.73 mmol). After stirring fora minute at 0° C., the ice bath was removed and stirring continued at rtfor 16 h. The reaction mixture was diluted with EtOAc, washed with water(3×), then brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The resulting solid was triturated with EtOAc (3×).The triturate was evaporated under reduced pressure and the residuepurified by silica gel chromatography eluting with 0-100% ethyl acetatein hexane to give Compound 218a (170 mg, 25%) as a white solid. MSm/z=394.1.0 (M+H). ¹H NMR (400 MHz, CDCl₃) δ 7.10 (dd, J=11.2, 9.2 Hz,1H), 6.69-6.54 (m, 1H), 4.41 (q, J=7.0 Hz, 2H), 3.82 (m, 3H), 3.72 (s,3H), 2.35 (t, J=7.8 Hz, 2H), 1.52 (td, J=7.5, 2.5 Hz, 2H), 1.40 (t,J=7.0 Hz, 3H), 0.78 (t, J=7.3 Hz, 3H)

Example 218.6-butyl-3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3-fluoro-2,6-dimethoxyphenyl)pyridine-2,4-diol(isomer 1) and Example 219.6-butyl-3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(3-fluoro-2,6-dimethoxyphenyl)pyridine-2,4-diol(isomer 2)

Example 218 and Example 219 were prepared from Compound 218a asdescribed in the general procedures for Example 1. The atropisomers wereseparated using chiral SFC after the final step (instrument: BergerMultigram II SFC; column: Chirapak AD-H, 21×250 mm ID, 5 micron; flowrate: 45 mL/min, 100 bar, 40° C.; mobile phase: 20% isopropanol/80% CO₂;wavelength: 220 nm) to give first eluting Example 218 (3 mg, 7%) as awhite solid, analytical SFC Rt=4.0 min (instrument: Aurora AnalyticalSFC; column: Chirapak AD-H, 4.6×250 mm ID, 5 micron; flow rate: 2mL/min, 150 bar, 35° C.; mobile phase: 25% isopropanol/75% CO₂; 220 nm),LCMS (Method C) Rt=2.20 min, m/z=514.0 (M+H), ¹H NMR (400 MHz, CDCl₃) δ7.24 (m, 4H), 7.06 (m, 1H), 6.54 (m, 1H), 4.20 (s, 2H), 4.01-3.91 (m,2H), 3.74 (m, 3H), 3.64 (s, 3H), 3.42 (m, 2H), 0.71 (t, J=7.2 Hz, 3H),Human APJ cAMP EC₅₀ Potency range B; and the second eluting Example 219(3 mg, 7%) as a white solid, analytical SFC Rt=5.2 min, LCMS (Method C)Rt=2.20 min, m/z=514.0 (M+H), ¹H NMR (400 MHz, CDCl₃) δ 7.24 (m, 4H),7.06 (m, 1H), 6.54 (m, 1H), 4.20 (s, 2H), 4.01-3.91 (m, 2H), 3.74 (m,3H), 3.64 (s, 3H), 3.42 (m, 2H), 0.71 (t, J=7.2 Hz, 3H), Human APJ cAMPEC₅₀ Potency range A.

Example 220 to Example 221 were prepared as described in the generalprocedure given for Example 218 and Example 219.

Example 222 and Example 223.3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5-(2-hydroxy-6-methoxyphenyl)pyridine-2,4-diol(Isomer 1) and3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-6-(ethoxymethyl)-5-(2-hydroxy-6-methoxyphenyl)pyridine-2,4-diol(Isomer 2)

To a solution of Example 90 (66 mg, 0.13 mmol) in DCM (2 mL) at −78° C.was added BBr₃ (1M in hexanes) (0.13 mL, 0.13 mmol) and the reactionmixture stirred for 15 min. The reaction mixture was cooled to 0° C. andstirred for 15 min. Additional BBr₃ (1M in hexanes) (0.07 mL, 0.07 mmol)was added and the reaction mixture stirred for 15 min. The reactionmixture was diluted with water (5 mL), extracted with DCM (3×5 mL) andthe combined organic portions dried over Na₂SO₄, filtered, thenconcentrated under reduced pressure. The residue was purified by prepHPLC then the atropisomers separated by chiral SFC (instrument: BergerMultigram II SFC; column: Chirapak AD-H, 21×250 mm ID, 5 micron; flowrate: 45 mL/min, 100 bar, 40° C.; mobile Phase: 35% isopropanol/65% CO₂;wavelength: 220 nm) to give Example 222 (11 mg, 16%) as isomer 1,analytical SFC Rt=7.2 min (instrument: Aurora Analytical SFC; column:Chirapak AD-H, 4.6×250 mm ID, 5 micron; flow rate: 2 mL/min, 150 bar,35° C.; mobile Phase: 35% isopropanol/65% CO₂; 220 nm): LCMS (Method D)Rt=0.90 min, m/z=484.1 [M+H]⁺, ¹H NMR (500 MHz, CD₃OD) δ 7.47-7.31 (min,4H), 7.22-7.08 (m, 1H), 6.61-6.44 (m, 2H), 4.39-4.25 (m, 2H), 4.18-4.07(m, 2H), 3.71 (s, 3H), 3.49-3.41 (m, 2H), 1.35-1.28 (m, 3H); Human APJcAMP EC₅₀ Potency range A; and Example 223 (11 mg, 16%) as isomer 2,analytical SFC Rt=12.6 min: LCMS (Method D) Rt=0.90 min, m/z=484.1[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 7.47-7.31 (m, 4H), 7.22-7.08 (m, 1H),6.61-6.44 (m, 2H), 4.39-4.25 (m, 2H), 4.18-4.07 (m, 2H), 3.71 (s, 3H),3.49-3.41 (m, 2H), 1.35-1.28 (m, 3H); Human APJ cAMP EC₅₀ Potency rangeB.

Example 224.3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-dimethylphenyl)pyridine-2,4-diol

Compound 224a. ethyl 2-bromo-2-(2,6-dimethylphenyl)acetate

To a solution of 1N LiHMDS in THF (4.4 mL, 4.4 mmol) in THF (7 mL) at−30° C. was added dropwise a solution of ethyl2-(2,6-dimethylphenyl)acetate (800 mg, 4.2 mmol) in THF (7 mL) and thereaction mixture stirred for 15 min. A solution of bromine (0.21 mL, 4.2mmol) in THF (7 mL) was added dropwise, then the temperature was allowedto warm to −5° C. over a 1 h period. The reaction mixture was quenchedby the addition of aqueous sodium thiosulfate then extracted with EtOAc.The organic extract was washed with satd NH₄Cl and brine, then dried(MgSO₄), filtered and concentrated under reduced pressure. The residuewas purified by silica gel chromatography eluting with 1 to 4%EtOAc/hexanes to give Compound 224a (740 mg, 2.7 mmol, 66% yield) as aclear colorless oil which solidified upon standing. MS m/z=271.0 (M+H).¹H NMR (400 MHz, CDCl₃) δ 7.16-7.09 (m, 1H), 7.06-7.01 (m, 2H), 5.95 (s,1H), 4.33-4.19 (m, 2H), 2.37 (s, 6H), 1.26 (t, J=7.2 Hz, 3H).

Compound 224b. (Z)-ethyl 3-amino-2-(2,6-dimethylphenyl)hept-2-enoate

To a solution of Compound 224a (130 mg, 0.47 mmol) in valeronitrile(0.50 mL, 4.7 mmol) was added activated zinc (46 mg, 0.71 mmol) followedby methanesulfonic acid (0.61 μl, 9.4 μmol) and the reaction mixturestirred at 40° C. for 1.5 h. The reaction mixture was allowed to cool toroom temperature then diluted with EtOAc and filtered. The filtrate waspoured into satd NaHCO₃ and extracted with EtOAc (3×). The combinedextracts were washed with brine, dried (Na₂SO₄), filtered andconcentrated under reduced pressure. The residue was purified by silicagel chromatography eluting with 0 to 15% EtOAc/hexanes to give Compound224b (74 mg, 0.27 mmol, 57% yield) as a clear oil. MS m/z=276.5 (M+H).1H NMR (400 MHz, CDCl₃) δ 7.11-6.99 (m, 3H), 4.06 (q, J=7.0 Hz, 2H),2.12 (s, 6H), 1.88-1.78 (m, 2H), 1.40-1.28 (m, 2H), 1.23-1.13 (m, 2H),1.10 (t, J=7.2 Hz, 3H), 0.75 (t, J=7.3 Hz, 3H).

Example 224.3-[5-(1,2-benzoxazol-3-ylmethyl)-1,3,4-oxadiazol-2-yl]-6-butyl-5-(2,6-dimethylphenyl)pyridine-2,4-diol

Example 224 was prepared from Compound 224b as described in the generalprocedure given for Example 1 in 33% yield. LCMS (Method A) Rt=2.12 min,m/z=471.1 (M+H). 1H NMR (500 MHz, DMSO-d6) δ 8.00 (d, J=7.6 Hz, 1H),7.81 (d, J=8.2 Hz, 1H), 7.72 (t, J=7.2 Hz, 1H), 7.44 (t, J=6.7 Hz, 1H),7.20 (d, J=7.3 Hz, 1H), 7.17-7.10 (m, 2H), 4.96 (s, 2H), 2.52 (br. s.,5H), 2.15 (br. s., 1H), 1.36 (br. s., 2H), 1.12 (d, J=7.0 Hz, 2H), 0.69(t, J=6.9 Hz, 3H). Human APJ cAMP EC50 Potency range A.

Example 225 and Example 226 were prepared as described in the generalprocedure given for Example 224.

Example 227.6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[1,2]oxazolo[4,5-b]pyridin-3-ylmethyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol

Compound 227a. 2-(isoxazolo[4,5-b]pyridin-3-yl)acetic acid

To a flask containing hydroxylamine hydrochloride (280 mg, 4.0 mmol) wasadded 10% aq sodium carbonate (1.5 mL, 1.5 mmol) and the mixture stirredfor 10 min. The solution was added to a flask containing4-hydroxy-2H-pyrano[3,2-b]pyridin-2-one (130 mg, 0.79 mmol; prepared asdescribed in DE2442666A1, 1975) and the reaction mixture stirred at 50°C. for 16 h. The reaction mixture was cooled to 10° C. then acidified topH 2 with dilute HCl. The reaction mixture was stirred for 0.5 h thenfiltered. The filtrate was purified by HPLC to give Compound 227a (80mg, 0.45 mmol, 57% yield) as a pale yellow solid. MS m/z=179.0 (M+H). ¹HNMR (500 MHz, DMSO-d₆) δ 12.92 (br. s., 1H), 8.80-8.72 (m, 1H), 8.28(dd, J=8.5, 1.1 Hz, 1H), 7.71 (dd, J=8.5, 4.4 Hz, 1H), 4.13 (s, 2H).

Example 227.6-butyl-5-(2,6-dimethoxyphenyl)-3-(5-{[1,2]oxazolo[4,5-b]pyridin-3-ylmethyl}-1,3,4-oxadiazol-2-yl)pyridine-2,4-diol

Example 227 was prepared from Compound 227a and Compound 1e as describedin the general procedure given for Example 1 in 68% yield. LCMS (MethodA) Rt=1.56 min, m/z=504.2 (M+H). ¹H NMR (500 MHz, DMSO-d₆) δ 8.77 (d,J=4.3 Hz, 1H), 8.34 (d, J=8.5 Hz, 1H), 7.75 (dd, J=8.4, 4.4 Hz, 1H),7.36 (t, J=8.4 Hz, 1H), 6.73 (d, J=8.5 Hz, 2H), 4.96 (s, 2H), 3.70 (s,6H), 2.15 (t, J=7.5 Hz, 2H), 1.40-1.27 (m, 2H), 1.15-1.03 (m, 2H), 0.66(t, J=7.3 Hz, 3H). Human APJ cAMP EC₅₀ Potency range A.

Example 228 was prepared as described in the general procedure given forExample 227.

Example 229.3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dihydroxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol

Example 229.3-{5-[(4-chlorophenyl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dihydroxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol

To a solution of Example 90 (86 mg, 0.17 mmol) in DCM (2 mL) at −78° C.was added BBr₃ (1.0M in hexanes) (0.17 mL, 0.17 mmol) and the reactionmixture stirred for 15 min. The reaction mixture was then placed in anice bath and stirred for 15 min. Additional BBr₃ (1.0M in hexanes) (0.09mL, 0.09 mmol) was added and the reaction mixture stirred 15 min thendiluted with water (5 mL), extracted with DCM (2×15 mL), dried overNa₂SO₄, then concentrated under reduced pressure. The residue waspurified by prep HPLC to give Example 229 (19 mg, 23% yield) as a whitesolid. LCMS (Method D) Rt=0.81 min, m/z=470.0 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 7.46-7.30 (m, 4H), 7.13-6.97 (m, 1H), 6.50-6.32 (m, 2H),4.41-4.31 (m, 2H), 4.28-4.22 (m, 2H), 3.51-3.46 (m, 2H), 1.24-1.12 (m,3H); Human APJ cAP EC₅₀ Potency range B

hAPJ cAMP LC/MS EC₅₀ Rt (min) Potency Method range Ex # Structure Name¹H NMR M + H (nM) 2

3-(5-benzyl- 1,3,4- oxadiazol-2- yl)-6-butyl- 5-(2,6- dimethoxy-4-methylphenyl) pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ 7.41- 7.34(m, 4H), 7.33- 7.27 (m, 1H), 6.55 (s, 2H), 4.37 (s, 2H), 3.66 (s, 6H),2.36 (s, 3H), 2.14 (t, J = 7.6 Hz, 2H), 1.33 (quin, J = 7.6 Hz, 2H),1.09 (sxt, J = 7.3 Hz, 2H), 0.68 (t, J = 7.3 Hz, 3H) 2.00 A 476.3 C 3

6-butyl-5- (2,6- dimethoxy- phenyl)-3- [5-(pyridin- 4-ylmethyl)- 1,3,4-oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ 8.56 (d,J = 5.2 Hz, 2H), 7.40 (d, J = 5.3 Hz, 2H), 7.35 (t, J = 8.3 Hz, 1H),6.72 (s, 2H), 4.44 (s, 2H), 3.68 (s, 6H), 2.13 (t, J = 7.5 Hz, 2H), 1.32(quin, J = 7.5 Hz, 2H), 1.15-1.01 (m, 2H), 0.65 (t, J = 7.3 Hz, 3H) 1.37A 463.2 B 4

6-butyl-5- (2,6- dimethoxy- phenyl)-3- [5-(2- phenylethyl)- 1,3,4-oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ 7.37-7.26 (m, 5H), 7.23- 7.16 (m, 1H), 6.70 (d, J = 8.4 Hz, 2H), 3.66 (s,6H), 3.24- 3.18 (m, 2H), 3.13- 3.03 (m, 2H), 2.11 (t, J = 7.3 Hz, 2H),1.40-1.25 (m, 2H), 1.12-1.01 (m, 2H), 0.64 (t, J = 7.3 Hz, 3H) 1.87 A476.2 B 5

6-butyl-3- {5-[(2- chlorophenyl) methyl]- 1,3,4- oxadiazol-2-yl}-5-(2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.50 (dd, J = 15.7, 4.5 Hz, 2H), 7.42-7.28 (m, 3H), 6.73 (d,J = 8.4 Hz, 2H), 4.47 (s, 2H), 3.75-3.62 (m, 6H), 2.15 (t, J = 7.6 Hz,2H), 1.35-1.24 (m, 2H), 1.14-1.02 (m, 2H), 0.66 (t, J = 7.3 Hz, 3H) 1.87A 496.2 B 6

6-butyl-5- (2,6- dimethoxy- phenyl)-3- {5-[(2- methoxy- phenyl) methyl]-1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ7.37- 7.28 (m, 2H), 7.24 (d, J = 7.1 Hz, 1H), 7.03 (d, J = 8.2 Hz, 1H),6.94 (t, J = 7.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 2H), 4.24 (s, 2H), 3.77(s, 3H), 3.67 (s, 6H), 2.13 (t, J = 7.7 Hz, 2H), 1.36-1.23 (m, 2H),1.12-1.00 (m, 2H), 0.64 (t, J = 7.3 Hz, 3H) 1.95 A 492.2 B 7

6-butyl-5- (2,6- dimethoxy- phenyl)-3- {5-[(3- methoxy- phenyl) methyl]-1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ7.34 (t, J = 8.4 Hz, 1H), 7.27 (t, J = 7.9 Hz, 1H), 6.96 (br. s., 1H),6.88 (dd, J = 16.7, 7.8 Hz, 2H), 6.72 (d, J = 8.3 Hz, 2H), 4.33 (s, 2H),3.75 (s, 3H), 3.67 (s, 6H), 2.13 (t, J = 7.5 Hz, 2H), 1.37-1.23 (m, 2H),1.11-0.99 (m, 2H), 0.64 (t, J = 7.3 Hz, 3H) 1.78 A 492.2 A 8

6-butyl-3- {5-[(4- chlorophenyl) methyl]- 1,3,4- oxadiazol- 2-yl}-5-(2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (400 MHz, CDCl3) δ10.41 (br. s., 1H), 7.37 (t, J = 8.4 Hz, 1H), 7.30 (s, 4H), 6.65 (d, J =8.4 Hz, 2H), 4.27 (s, 2H), 3.75 (s, 6H), 2.37- 2.29 (m, 2H), 1.49 (dt, J= 15.3, 7.5 Hz, 2H), 1.27-1.15 (m, 2H), 0.76 (t, J = 7.4 Hz, 3H) 2.19 C496.1 A 9

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[(4- methoxy- phenyl) methyl]-1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ7.37- 7.32 (m, 1H), 7.26 (d, J = 8.5 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H),6.71 (d, J = 8.4 Hz, 2H), 4.26 (s, 2H), 3.73 (s, 3H), 3.67 (s, 6H), 2.12(t, J = 7.6 Hz, 2H), 1.30 (quin, J = 7.5 Hz, 2H), 1.12-0.98 (m, 2H),0.64 (t, J = 7.3 Hz, 3H) 1.78 A 492.2 A 10

6-butyl-3- [5-(3- chloro- phenyl)- 1,3,4- oxadiazol- 2-yl]-5-(2,6-dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ 8.02(br. s., 2H), 7.77- 7.60 (m, 2H), 7.34 (br. s., 1H), 6.72 (d, J = 8.2Hz, 2H), 3.74-3.64 (m, 6H), 2.14 (br. s., 2H), 1.40-1.26 (m, 2H),1.14-1.04 (m, 2H), 0.66 (t, J = 7.3 Hz, 3H) 1.96 A 482.1 B 11

6-butyl-3- [5-(2- chloro- phenyl)- 1,3,4- oxadiazol- 2-yl]-5-(2,6-dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ 8.01(d, J = 7.6 Hz, 1H), 7.79-7.56 (m, 3H), 7.36 (t, J = 8.3 Hz, 1H), 6.74(d, J = 8.4 Hz, 2H), 3.70 (s, 6H), 2.16 (t, J = 7.6 Hz, 2H), 1.34 (t, J= 7.2 Hz, 2H), 1.13-1.02 (m, 2H), 0.66 (t, J = 7.3 Hz, 3H) 1.85 A 482.1C 12

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-[5- (pyrazin-2- yl)-1,3,4-oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ 9.39 (s,1H), 8.89 (s, 2H), 7.36 (t, J = 8.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 2H),3.70 (s, 6H), 2.16 (t, J = 7.7 Hz, 2H), 1.41-1.27 (m, 2H), 1.14-1.02 (m,2H), 0.66 (t, J = 7.4 Hz, 3H) 1.30 A 450.2 C 13

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-[5-(1- phenyl- cyclo- propyl)-1,3,4- oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ7.48- 7.22 (m, 6H), 6.71 (d, J = 8.4 Hz, 2H), 3.67 (s, 6H), 2.12 (t, J =7.6 Hz, 2H), 1.70-1.60 (m, 2H), 1.55-1.46 (m, 2H), 1.30 (quin, J = 7.4Hz, 2H), 1.11-1.00 (m, 2H), 0.64 (t, J = 7.3 Hz, 3H) 1.92 A 488.2 B 14

6-butyl-3- (5-cyclo- propyl- 1,3,4- oxadiazol- 2-yl)-5- (2,6- dimethoxy-phenyl) pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ 7.34 (t, J = 8.4Hz, 1H), 6.71 (d, J = 8.4 Hz, 2H), 3.67 (s, 6H), 2.34-2.22 (m, 1H), 2.13(t, J = 7.7 Hz, 2H), 1.31 (quin, J = 7.4 Hz, 2H), 1.20- 1.13 (m, 2H),1.10- 1.00 (m, 4H), 0.64 (t, J = 7.3 Hz, 3H) 1.65 A 412.2 C 15

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-[5-(2- phenyl- propan-2-yl)-1,3,4- oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6)δ 7.38- 7.32 (m, 3H), 7.31- 7.25 (m, 3H), 6.72 (d, J = 8.4 Hz, 2H), 3.67(s, 6H), 2.12 (t, J = 7.6 Hz, 2H), 1.78 (s, 6H), 1.35- 1.24 (m, 2H),1.12- 0.98 (m, 2H), 0.63 (t, J = 7.3 Hz, 3H) 2.00 A 490.3 A 17

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-[5- (phenoxy- methyl)- 1,3,4-oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ 7.42-7.29 (m, 3H), 7.10 (d, J = 8.0 Hz, 2H), 7.03 (t, J = 7.2 Hz, 1H), 6.73(d, J = 8.3 Hz, 2H), 5.47 (s, 2H), 3.69 (s, 6H), 2.15 (t, J = 7.5 Hz,2H), 1.40-1.27 (m, 2H), 1.15-0.99 (m, 2H), 0.65 (t, J = 7.2 Hz, 3H) 1.75A 478.2 B 18

3-(5-benzyl- 1,3,4- oxadiazol- 2-yl)-6- (but-3-en- 1-yl)-5- (2,6-dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (400 MHz, CDCl3) δ 11.10(br. s., 1H), 7.41-7.25 (m, 6H), 6.66 (d, J = 8.4 Hz, 2H), 5.69 (ddt, J= 17.0, 10.3, 6.6 Hz, 1H), 5.00-4.88 (m, 2H), 4.29 (s, 2H), 3.75 (s,6H), 2.50-2.41 (m, 2H), 2.28 (q, J = 7.0 Hz, 2H) 2.05 C 460.1 B 19

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-[5-(5- methyl-1H- pyrazol-3-yl)-1,3,4- oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6)δ 7.36 (t, J = 8.2 Hz, 1H), 6.74 (d, J = 8.5 Hz, 2H), 6.67 (br. s., 1H),3.70 (s, 6H), 2.34 (br. s., 3H), 2.20-2.11 (m, 2H), 1.34 (dd, J = 14.6,7.3 Hz, 2H), 1.10 (dd, J = 14.6, 7.3 Hz, 2H), 0.67 (t, J = 7.2 Hz, 3H)1.76 A 452.3 C 20

3-[5-(1,2- benzoxazol- 3-ylmethyl)- 1,3,4- oxadiazol- 2-yl]-6- butyl-5-(2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (400 MHz, CDCl3) δ11.48 (br. s., 1H), 7.86 (d, J = 8.1 Hz, 1H), 7.61- 7.53 (m, 2H), 7.41-7.31 (m, 2H), 6.65 (d, J = 8.4 Hz, 2H), 4.71 (s, 2H), 3.74 (s, 6H),2.42-2.28 (m, 2H), 1.50 (quin, J = 7.6 Hz, 2H), 1.28-1.14 (m, 2H), 0.74(t, J = 7.3 Hz, 3H) 2.06 C 503.1 A 21

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-[5- (pyrazin-2- ylmethyl)- 1,3,4-oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ 8.74 (s,1H), 8.63-8.53 (m, 2H), 7.18 (t, J = 8.2 Hz, 1H), 6.59 (d, J = 8.2 Hz,2H), 4.44 (s, 2H), 3.62 (s, 6H), 1.91 (d, J = 7.9 Hz, 2H), 1.33-1.25 (m,2H), 1.12-1.03 (m, 2H), 0.65 (t, J = 7.3 Hz, 3H) 1.34 A 464.2 A 22

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-[5- (pyrimidin- 5-ylmethyl)-1,3,4- oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ9.14 (s, 1H), 8.86 (s, 2H), 7.29 (t, J = 7.8 Hz, 1H), 6.68 (d, J = 8.2Hz, 2H), 4.42 (br. s., 2H), 3.66 (s, 6H), 2.07 (br. s., 2H), 1.38-1.27(m, 2H), 1.14-1.02 (m, 2H), 0.66 (t, J = 7.3 Hz, 3H) 1.57 B 464.3 B 23

6-butyl-3- {5-[(3- chlorophenyl) methyl]- 1,3,4- oxadiazol- 2-yl}-5-(2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ7.48 (s, 1H), 7.44-7.30 (m, 4H), 6.73 (d, J = 8.4 Hz, 2H), 4.40 (s, 2H),3.68 (s, 6H), 2.14 (t, J = 7.7 Hz, 2H), 1.32 (quin, J = 7.5 Hz, 2H),1.08 (sxt, J = 7.3 Hz, 2H), 0.65 (t, J = 7.4 Hz, 3H) 1.92 A 496.2 A 24

6-butyl-3- {5-[difluoro (phenyl) methyl]- 1,3,4- oxadiazol- 2-yl}-5-(2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ7.73 (d, J = 7.6 Hz, 2H), 7.70-7.65 (m, 1H), 7.64-7.58 (m, 2H), 7.35 (t,J = 8.2 Hz, 1H), 6.73 (d, J = 8.2 Hz, 2H), 3.69 (s, 6H), 2.15 (t, J =7.0 Hz, 2H), 1.33 (quin, J = 7.5 Hz, 2H), 1.09 (sxt, J = 7.3 Hz, 2H),0.66 (t, J = 7.3 Hz, 3H) 1.97 A 498.4 B 25

3-[5-(1,3- benzoxazol- 2-ylmethyl)- 1,3,4- oxadiazol- 2-yl]-6- butyl-5-(2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ7.76 (d, J = 7.3 Hz, 2H), 7.48-7.33 (m, 3H), 6.74 (d, J = 8.5 Hz, 2H),4.95 (s, 2H), 3.70 (s, 6H), 2.15 (t, J = 7.5 Hz, 2H), 1.38-1.30 (m, 2H),1.13-1.05 (m, 2H), 0.66 (t, J = 7.2 Hz, 3H) 1.71 A 503.4 A 26

3-[5-(1,2- benzoxazol- 3-ylmethyl)- 1,3,4- oxadiazol- 2-yl]-6- butyl-5-(2,6- dimethoxy- 4-methyl- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.96 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 8.5 Hz, 1H), 7.74-7.66(m, 1H), 7.42 (t, J = 7.3 Hz, 1H), 6.55 (s, 2H), 4.93 (s, 2H), 3.67 (s,6H), 2.36 (s, 3H), 2.15 (t, J = 7.5 Hz, 2H), 1.38- 1.30 (m, 2H), 1.14-1.05 (m, 2H), 0.68 (t, J = 7.2 Hz, 3H) 1.96 A 517.4 A 27

3-[5-(1,2- benzoxazol- 3-ylmethyl)- 1,3,4- oxadiazol- 2-yl]-6-(but-3-en- 1-yl)-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR(500 MHz, DMSO-d6) δ 11.78 (br. s., 1H), 7.97 (d, J = 7.9 Hz, 1H), 7.79(d, J = 8.2 Hz, 1H), 7.75-7.66 (m, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.36(t, J = 8.1 Hz, 1H), 6.73 (d, J = 8.2 Hz, 2H), 5.69-5.57 (m, 1H), 4.93(br. s., 2H), 4.90-4.81 (m, 2H), 3.35 (br. s., 6H), 2.24 (d, J = 7.0 Hz,2H), 2.11 (d, J = 6.4 Hz, 2H) 1.75 A 501.4 A 28

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[2-(5- phenyl- 1,3-oxazol-2-yl)ethyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.66 (d, J = 7.0 Hz, 2H), 7.56 (br. s., 1H), 7.45 (t, J = 7.0Hz, 2H), 7.35 (br. s., 2H), 6.73 (d, J = 8.2 Hz, 2H), 3.70 (br. s., 6H),3.47 (d, J = 6.4 Hz, 2H), 3.37 (br. s., 2H), 2.16 (br. s., 2H), 1.34(br. s., 2H), 1.10 (d, J = 6.7 Hz, 2H), 0.67 (t, J = 6.6 Hz, 3H) 1.91 A543.4 B 29

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[2-(1- methyl-1H- imidazol-2-yl)ethyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.56 (br. s., 1H), 7.50 (br. s., 1H), 7.36 (br. s., 1H), 6.73(d, J = 7.6 Hz, 2H), 3.83 (br. s., 3H), 3.69 (br. s., 6H), 3.47 (br. s.,4H), 2.15 (br. s., 2H), 1.33 (br. s., 2H), 1.09 (br. s., 2H), 0.66 (br.s., 3H) 1.34 A 480.4 A 30

6-butyl-3- {5-[(6- chloro- pyridin- 3-yl) methyl]- 1,3,4- oxadiazol-2-yl}-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 8.48 (br. s., 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.55 (d, J = 7.9Hz, 1H), 7.35 (t, J = 8.1 Hz, 1H), 6.73 (d, J = 8.2 Hz, 2H), 4.46 (br.s., 2H), 3.69 (br. s., 6H), 2.15 (br. s., 2H), 1.33 (br. s., 2H), 1.09(d, J = 6.7 Hz, 2H), 0.66 (t, J = 6.6 Hz, 3H) 1.62 A 497.3 A 31

6-butyl-3- {5-[2-(4- chloro- phenyl) propan-2- yl]-1,3,4- oxadiazol-2-yl}-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.42 (d, J = 7.6 Hz, 2H), 7.34 (d, J = 7.6 Hz, 3H), 6.73 (d,J = 7.9 Hz, 2H), 3.69 (br. s., 6H), 2.14 (br. s., 2H), 1.79 (br. s.,6H), 1.32 (br. s., 2H), 1.08 (d, J = 6.4 Hz, 2H), 0.66 (br. s., 3H) 2.16A 524.4 A 32

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[(4- fluoro- phenyl) methyl]-1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ7.42 (br. s., 2H), 7.38- 7.31 (m, 1H), 7.20 (t, J = 8.1 Hz, 2H), 6.73(d, J = 7.9 Hz, 2H), 4.38 (br. s., 2H), 3.69 (br. s., 6H), 2.15 (br. s.,2H), 1.33 (br. s., 2H), 1.09 (d, J = 6.7 Hz, 2H), 0.66 (t, J = 6.4 Hz,3H) 1.83 A 480.4 A 33

6-butyl-3- {5-[(3,4- dichloro- phenyl) methyl]- 1,3,4- oxadiazol-2-yl}-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.64 (br. s., 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.37-7.20 (m,2H), 6.65 (d, J = 7.9 Hz, 2H), 4.35 (br. s., 2H), 3.62 (br. s., 6H),2.07 (br. s., 2H), 1.26 (br. s., 2H), 1.01 (d, J = 6.7 Hz, 2H), 0.59 (t,J = 6.7 Hz, 3H) 2.07 A 530.3 A 34

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-(5-{[4- fluoro-3- (trifluoro-methyl) phenyl] methyl}- 1,3,4- oxadiazol- 2-yl) pyridine-2,4- diol 1HNMR (500 MHz, DMSO-d6) δ 7.89 (d, J = 5.2 Hz, 1H), 7.78 (br. s., 1H),7.53 (t, J = 9.5 Hz, 1H), 7.39-7.29 (m, 1H), 6.72 (d, J = 7.9 Hz, 2H),4.50 (br. s., 2H), 3.69 (br. s., 6H), 2.14 (br. s., 2H), 1.33 (br. s.,2H), 1.09 (d, J = 7.0 Hz, 2H), 0.73- 0.60 (m, 3H) 2.03 A 548.3 B 35

6-butyl-3- {5-[(2,4- dichloro- phenyl) methyl]- 1,3,4- oxadiazol-2-yl}-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.70 (br. s., 1H), 7.58- 7.52 (m, 1H), 7.50- 7.45 (m, 1H),7.35 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 7.9 Hz, 2H), 4.47 (br. s., 2H),3.69 (br. s., 6H), 2.15 (br. s., 2H), 1.33 (br. s., 2H), 1.09 (d, J =6.7 Hz, 2H), 0.71- 0.61 (m, 3H) 2.07 A 530.3 A 36

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[(3,5- dimethyl- 1H- pyrazol-4-yl) methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500MHz, DMSO-d6) δ 7.35 (t, J = 7.9 Hz, 1H), 6.73 (d, J = 8.2 Hz, 2H), 4.06(br. s., 2H), 3.69 (br. s., 6H), 2.20 (br. s., 6H), 2.15 (br. s., 2H),1.33 (br. s., 2H), 1.09 (d, J = 6.7 Hz, 2H), 0.66 (t, J = 6.3 Hz, 3H)1.47 A 480.4 B 37

4-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]-1,3,4- oxadiazol- 2-yl} methyl) benzonitrile 1H NMR (500 MHz,DMSO-d6) δ 7.85 (d, J = 7.6 Hz, 2H), 7.59 (d, J = 7.3 Hz, 2H), 7.34 (t,J = 7.3 Hz, 1H), 6.72 (d, J = 7.6 Hz, 2H), 4.51 (br. s., 2H), 3.69 (br.s., 6H), 2.13 (br. s., 2H), 1.33 (br. s., 2H), 1.09 (d, J = 7.0 Hz, 2H),0.66 (t, J = 6.4 Hz, 3H) 1.73 A 487.4 A 38

6-butyl-3- {5-[(3,4- difluoro- phenyl) methyl]- 1,3,4- oxadiazol-2-yl}-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.47- 7.39 (m, 1H), 7.39- 7.32 (m, 1H), 7.28 (t, J = 8.1 Hz,1H), 7.17 (br. s., 1H), 6.66 (d, J = 7.9 Hz, 2H), 4.33 (br. s., 2H),3.62 (br. s., 6H), 2.07 (br. s., 2H), 1.26 (br. s., 2H), 1.02 (d, J =7.0 Hz, 2H), 0.59 (t, J = 6.6 Hz, 3H) 1.86 A 498.4 A 39

6-butyl-3- (5-{[2-(4- chloro- phenyl)- 1,3- thiazol-4- yl]methyl}-1,3,4- oxadiazol- 2-yl)-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol1H NMR (500 MHz, DMSO-d6) δ 7.94 (d, J = 7.6 Hz, 2H), 7.72 (br. s., 1H),7.56 (d, J = 7.9 Hz, 2H), 7.35 (t, J = 7.8 Hz, 1H), 6.73 (d, J = 7.9 Hz,2H), 4.58 (br. s., 2H), 3.69 (br. s., 6H), 2.15 (br. s., 2H), 1.33 (br.s., 2H), 1.09 (d, J = 6.7 Hz, 2H), 0.66 (t, J = 6.3 Hz, 3H) 2.12 A 579.3B 40

6-butyl-3- {5-[1-(4- chloro- phenyl) ethyl]- 1,3,4- oxadiazol- 2-yl}-5-(2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6)δ 7.48- 7.41 (m, 2H), 7.40- 7.29 (m, 3H), 6.72 (d, J = 7.9 Hz, 2H), 4.62(d, J = 6.1 Hz, 1H), 3.69 (br. s., 6H), 2.13 (br. s., 2H), 1.67 (d, J =6.1 Hz, 3H), 1.32 (br. s., 2H), 1.08 (d, J = 7.0 Hz, 2H), 0.66 (t, J =6.4 Hz, 3H) 2.07 A 510.3 A 41

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[(4- methyl- 1,2,5- oxadiazol-3-yl) methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500MHz, DMSO-d6) δ 7.35 (br. s., 1H), 6.73 (d, J = 7.3 Hz, 2H), 4.73 (br.s., 2H), 3.69 (br. s., 6H), 2.42 (br. s., 3H), 2.14 (br. s., 2H), 1.34(br. s., 2H), 1.09 (d, J = 6.1 Hz, 2H), 0.66 (br. s., 3H) 1.57 A 468.4 A42

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-[5-(4- fluoro- phenoxy- methyl)-1,3,4- oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ7.36 (t, J = 7.8 Hz, 1H), 7.22-7.10 (m, 4H), 6.73 (d, J = 7.9 Hz, 2H),5.47 (br. s., 2H), 3.70 (br. s., 6H), 2.15 (br. s., 2H), 1.34 (br. s.,2H), 1.09 (d, J = 6.7 Hz, 2H), 0.66 (t, J = 6.6 Hz, 3H) 1.84 A 496.4 B43

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-[5-(1H- indazol-3- ylmethyl)-1,3,4- oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ7.80 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.42-7.30 (m, 2H),7.12 (br. s., 1H), 6.72 (d, J = 7.6 Hz, 2H), 4.71 (br. s., 2H), 3.69(br. s., 6H), 2.14 (br. s., 2H), 1.32 (br. s., 2H), 1.08 (d, J = 6.7 Hz,2H), 0.65 (br. s., 3H) 1.68 A 502.4 A 44

4-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]-1,3,4- oxadiazol- 2-yl} methyl)- 1,2- dihydro- phthalazin- 1-one1H NMR (500 MHz, DMSO-d6) δ 8.30 (d, J = 7.3 Hz, 1H), 8.06 (d, J = 7.3Hz, 1H), 7.98 (t, J = 6.9 Hz, 1H), 7.93-7.85 (m, 1H), 7.35 (t, J = 7.6Hz, 1H), 6.73 (d, J = 7.9 Hz, 2H), 4.78 (br. s., 2H), 3.34 (br. s., 6H),2.14 (br. s., 2H), 1.33 (br. s., 2H), 1.09 (d, J = 6.7 Hz, 2H), 0.66 (t,J = 6.4 Hz, 3H) 1.46 A 530.4 B 45

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5- [methoxy (phenyl) methyl]-1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ7.51 (d, J = 6.7 Hz, 2H), 7.43 (d, J = 7.3 Hz, 3H), 7.35 (t, J = 7.9 Hz,1H), 6.72 (d, J = 7.9 Hz, 2H), 5.86 (br. s., 1H), 3.69 (br. s., 6H),3.41 (br. s., 3H), 2.15 (br. s., 2H), 1.33 (br. s., 2H), 1.09 (d, J =7.0 Hz, 2H), 0.66 (t, J = 6.6 Hz, 3H) 1.81 A 492.4 B 46

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[(2- phenyl- 1,3- thiazol-4-yl)methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.93 (d, J = 3.7 Hz, 2H), 7.69 (br. s., 1H), 7.50 (br. s.,3H), 7.36 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 7.9 Hz, 2H), 4.59 (br. s.,2H), 3.69 (br. s., 6H), 2.15 (br. s., 2H), 1.33 (br. s., 2H), 1.09 (d, J= 6.7 Hz, 2H), 0.71-0.60 (m, 3H) 1.95 A 545.3 A 47

3-{5-[2- (1,3- benzoxazol- 2-yl)ethyl]- 1,3,4- oxadiazol- 2-yl}-6-butyl-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.69 (d, J = 6.7 Hz, 2H), 7.36 (br. s., 3H), 6.73 (d, J = 7.9Hz, 2H), 3.69 (br. s., 6H), 3.53 (d, J = 10.7 Hz, 4H), 2.15 (br. s.,2H), 1.34 (br. s., 2H), 1.09 (d, J = 6.7 Hz, 2H), 0.66 (t, J = 6.4 Hz,3H) 1.77 A 517.4 A 48

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[(4- fluoro-3- methoxy-phenyl) methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500MHz, DMSO-d6) δ 7.35 (t, J = 7.8 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 7.19(t, J = 9.5 Hz, 1H), 6.92 (br. s., 1H), 6.73 (d, J = 7.9 Hz, 2H), 4.36(br. s., 2H), 3.86 (br. s., 3H), 3.69 (br. s., 6H), 2.15 (br. s., 2H),1.33 (br. s., 2H), 1.09 (d, J = 6.4 Hz, 2H), 0.66 (br. s., 3H) 1.84 A510.4 A 49

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-[5-(1,3- thiazol-5- ylmethyl)-1,3,4- oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ9.08 (br. s., 1H), 7.91 (br. s., 1H), 7.35 (t, J = 7.8 Hz, 1H), 6.73 (d,J = 7.9 Hz, 2H), 4.72 (br. s., 2H), 3.69 (br. s., 6H), 2.14 (br. s.,2H), 1.33 (br. s., 2H), 1.09 (d, J = 6.1 Hz, 2H), 0.66 (br. s., 3H) 1.44A 469.3 C 50

6-butyl-3- [5-(3,4- dichloro- phenoxy- methyl)- 1,3,4- oxadiazol-2-yl]-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.59 (d, J = 8.5 Hz, 1H), 7.48 (br. s., 1H), 7.36 (t, J = 7.5Hz, 1H), 7.14 (d, J = 8.5 Hz, 1H), 6.73 (d, J = 7.6 Hz, 2H), 5.56 (br.s., 2H), 3.70 (br. s., 6H), 2.15 (br. s., 2H), 1.34 (br. s., 2H), 1.09(d, J = 6.4 Hz, 2H), 0.66 (br. s., 3H) 2.08 A 546.3 B 51

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[(3- methyl- 1,2-oxazol- 5-yl)methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.35 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 7.6 Hz, 2H), 6.40 (br.s., 1H), 4.66 (br. s., 2H), 3.70 (br. s., 6H), 2.24 (br. s., 3H), 2.15(br. s., 2H), 1.34 (br. s., 2H), 1.09 (d, J = 6.4 Hz, 2H), 0.66 (br. s.,3H) 1.51 A 467.4 A 52

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-(5-{2-[3- (pyrazin- 2-yl)-1,2,4-oxadiazol- 5-yl]ethyl}- 1,3,4- oxadiazol- 2-yl) pyridine-2,4- diol 1HNMR (500 MHz, DMSO-d6) δ 9.26 (br. s., 1H), 8.87 (br. s., 2H), 7.34 (t,J = 7.6 Hz, 1H), 6.72 (d, J = 7.9 Hz, 2H), 3.69 (br. s., 6H), 3.60 (d, J= 14.6 Hz, 4H), 2.14 (br. s., 2H), 1.33 (br. s., 2H), 1.09 (d, J = 6.7Hz, 2H), 0.70-0.60 (m, 3H) 1.52 A 546.4 A 53

6-butyl-3- [5-(4- chloro- phenoxy- methyl)- 1,3,4- oxadiazol- 2-yl]-5-(2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ7.44- 7.31 (m, 3H), 7.15 (d, J = 7.6 Hz, 2H), 6.73 (d, J = 7.9 Hz, 2H),5.50 (br. s., 2H), 3.70 (br. s., 6H), 2.15 (br. s., 2H), 1.34 (br. s.,2H), 1.09 (d, J = 6.7 Hz, 2H), 0.66 (br. s., 3H) 1.94 A 512.3 B 54

6-butyl-3- {5-[2-(4- chloro- phenyl)- 2-methyl- propyl]- 1,3,4-oxadiazol- 2-yl}-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR(500 MHz, DMSO-d6) δ 7.45 (br. s., 4H), 7.35 (t, J = 7.6 Hz, 1H), 6.72(d, J = 7.9 Hz, 2H), 3.68 (br. s., 6H), 3.38-3.21 (m, 2H), 2.14 (br. s.,2H), 1.32 (br. s., 2H), 1.09 (d, J = 6.4 Hz, 2H), 0.98 (br. s., 3H),0.83 (br. s., 3H), 0.66 (br. s., 3H) 2.35 A 538.4 A 55

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-(5-{[3- (pyridin-2- yl)-1,2,4-oxadiazol- 5-yl] methyl}- 1,3,4- oxadiazol- 2-yl) pyridine-2,4- diol 1HNMR (500 MHz, DMSO-d6) δ 8.81- 8.75 (m, 1H), 8.13- 8.07 (m, 1H), 8.05-7.99 (m, 1H), 7.63 (ddd, J = 7.6, 4.8, 1.4 Hz, 1H), 7.36 (t, J = 8.4 Hz,1H), 6.74 (d, J = 8.5 Hz, 2H), 5.12 (s, 2H), 3.70 (s, 7H), 2.21-2.11 (m,2H), 1.39-1.30 (m, 2H), 1.09 (sxt, J = 7.3 Hz, 2H), 0.66 (t, J = 7.3 Hz,1H) 0.93 D 531.2 A 56

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-(5-{[4- (trifluoro- methoxy)phenyl] methyl}- 1,3,4- oxadiazol- 2-yl) pyridine-2,4- diol 1H NMR (500MHz, DMSO-d6) δ 7.44 (d, J = 7.3 Hz, 2H), 7.35-7.23 (m, 3H), 6.65 (d, J= 7.6 Hz, 2H), 4.37 (br. s., 2H), 3.62 (br. s., 6H), 2.07 (br. s., 2H),1.26 (br. s., 2H), 1.01 (d, J = 6.4 Hz, 2H), 0.59 (br. s., 3H) 2.09 A546.4 A 57

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-(5-{[3- fluoro-5- (trifluoro-methyl) phenyl] methyl}- 1,3,4- oxadiazol- 2-yl) pyridine-2,4- diol 1HNMR (500 MHz, DMSO-d6) δ 7.72 (br. s., 1H), 7.68- 7.60 (m, 2H), 7.42-7.27 (m, 1H), 6.73 (d, J = 7.9 Hz, 2H), 4.56 (br. s., 2H), 3.69 (br. s.,6H), 2.15 (br. s., 2H), 1.34 (br. s., 2H), 1.09 (d, J = 6.4 Hz, 2H),0.66 (br. s., 3H) 2.07 A 548.3 B 58

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[2-(1- methyl- 1H-1,3- benzo-diazol-2- yl)ethyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR(500 MHz, DMSO-d6) δ 7.56 (d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.6 Hz, 1H),7.39-7.32 (m, 1H), 7.25-7.19 (m, 1H), 7.17 (d, J = 7.0 Hz, 1H), 6.73 (d,J = 7.9 Hz, 2H), 3.81 (br. s., 3H), 3.69 (br. s., 6H), 3.55 (br. s.,2H), 3.44 (br. s., 2H), 2.16 (br. s., 2H), 1.34 (br. s., 2H), 1.09 (d, J= 6.7 Hz, 2H), 0.67 (br. s., 3H) 1.67 A 530.4 A 59

6-butyl-3- {5-[(2- chloro- pyridin- 4-yl) methyl]- 1,3,4- oxadiazol-2-yl}-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 8.41 (br. s., 1H), 7.60 (br. s., 1H), 7.45 (br. s., 1H), 7.36(t, J = 7.8 Hz, 1H), 6.73 (d, J = 7.9 Hz, 2H), 4.51 (br. s., 2H), 3.69(br. s., 6H), 2.15 (br. s., 2H), 1.34 (br. s., 2H), 1.09 (d, J = 6.4 Hz,2H), 0.66 (br. s, 3H) 1.62 A 497.4 A 60

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-(5-{2- [3-(4- methoxy- phenyl)-1,2,4- oxadiazol- 5-yl]ethyl}- 1,3,4- oxadiazol- 2-yl) pyridine-2,4-diol 1H NMR (500 MHz, DMSO-d6) δ 7.86 (d, J = 8.2 Hz, 2H), 7.28 (t, J =7.8 Hz, 1H), 7.03 (d, J = 6.4 Hz, 2H), 6.65 (d, J = 7.9 Hz, 2H), 3.76(br. s., 3H), 3.62 (br. s., 6H), 3.47 (br. s., 4H), 2.08 (br. s., 2H),1.27 (br. s., 2H), 1.02 (d, J = 6.4 Hz, 2H), 0.59 (br. s., 3H) 1.92 A574.4 B 61

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-[5- (1,2,3,4- tetrahydro-isoquinolin- 1-yl)-1,3,4- oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR(500 MHz, DMSO-d6) δ 7.36- 7.25 (m, 3H), 7.21 (d, J = 12.2 Hz, 2H), 6.66(d, J = 7.9 Hz, 2H), 6.29 (br. s., 1H), 3.62 (br. s., 6H), 3.49 (br. s.,2H), 3.05 (br. s., 2H), 2.09 (br. s., 2H), 1.26 (br. s., 2H), 1.02 (d, J= 6.1 Hz, 2H), 0.59 (br. s., 3H) 1.69 A 503.4 A 62

6-butyl-3- {5-[2-(3,4- dichloro- phenyl) propan-2- yl]-1,3,4- oxadiazol-2-yl}-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.68- 7.58 (m, 2H), 7.35 (t, J = 7.8 Hz, 1H), 7.29 (d, J =8.5 Hz, 1H), 6.73 (d, J = 7.9 Hz, 2H), 3.69 (br. s., 6H), 2.14 (br. s.,2H), 1.80 (br. s., 6H), 1.32 (br. s., 2H), 1.08 (d, J = 6.7 Hz, 2H),0.66 (br. s., 3H) 2.30 A 558.3 A 63

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[(2- methyl- 2H-1,2,3,4-tetrazol- 5-yl) methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1HNMR (500 MHz, DMSO-d6) δ 7.33- 7.22 (m, 1H), 6.66 (d, J = 7.9 Hz, 2H),4.86 (br. s., 2H), 4.05 (br. s., 3H), 3.62 (br. s., 6H), 2.08 (br. s.,2H), 1.27 (br. s., 2H), 1.02 (d, J = 6.4 Hz, 2H), 0.59 (br. s., 3H) 1.32A 468.4 A 64

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-[5-(2- methyl-1- phenyl-propan-2- yl)-1,3,4- oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500MHz, DMSO-d6) δ 7.36 (t, J = 7.6 Hz, 1H), 7.28-7.14 (m, 3H), 7.04 (d, J= 5.5 Hz, 2H), 6.74 (d, J = 7.9 Hz, 2H), 3.71 (br. s., 6H), 3.05 (br.s., 2H), 2.17 (br. s., 2H), 1.40 (br. s., 6H), 1.35 (br. s., 2H), 1.11(d, J = 6.4 Hz, 2H), 0.68 (br. s., 3H) 2.12 A 504.4 A 65

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[4- (trifluoro- methyl)phenoxy- methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500MHz, DMSO-d6) δ 7.65 (d, J = 7.9 Hz, 2H), 7.28 (t, J = 8.1 Hz, 1H), 7.24(d, J = 7.9 Hz, 2H), 6.66 (d, J = 7.6 Hz, 2H), 5.54 (br. s., 2H), 3.62(br. s., 6H), 2.08 (br. s., 2H), 1.27 (br. s., 2H), 1.02 (d, J = 6.7 Hz,2H), 0.59 (br. s., 3H) 2.01 A 546.3 B 66

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[(5- phenyl- 4H-1,2,4-triazol-3- yl)methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR(400 MHz, DMSO-d6) δ 7.99 (dd, J = 8.0, 1.4 Hz, 2H), 7.56-7.45 (m, 3H),7.36 (t, J = 8.4 Hz, 1H), 6.73 (d, J = 8.6 Hz, 2H), 4.57 (br. s., 2H),3.70 (s, 6H), 2.21- 2.08 (m, 2H), 1.33 (t, J = 7.7 Hz, 2H), 1.14-1.03(m, 2H), 0.66 (t, J = 7.3 Hz, 3H) 2.00 C 529.2 A 67

6-butyl-3- [5-(cyclo- hexyl- methyl)- 1,3,4- oxadiazol- 2-yl]-5- (2,6-dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ 7.35(t, J = 7.6 Hz, 1H), 6.73 (d, J = 7.9 Hz, 2H), 3.69 (br. s., 6H), 2.83(d, J = 5.2 Hz, 2H), 2.15 (br. s., 2H), 1.86-1.56 (m, 6H), 1.39-0.99 (m,9H), 0.67 (br. s., 3H) 2.11 A 468.5 A 68

6-butyl-3- {5-[2-(4- chloro- phenyl) ethyl]- 1,3,4- oxadiazol- 2-yl}-5-(2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ7.35 (br. s., 5H), 6.73 (d, J = 7.9 Hz, 2H), 3.69 (br. s., 6H), 3.26 (d,J = 5.8 Hz, 2H), 3.10 (br. s., 2H), 2.15 (br. s., 2H), 1.34 (br. s.,2H), 1.09 (d, J = 6.7 Hz, 2H), 0.66 (br. s., 3H) 2.05 A 510.4 A 69

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-[5- (oxan-4- ylmethyl)- 1,3,4-oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ 7.35 (t,J = 7.2 Hz, 1H), 6.73 (d, J = 7.6 Hz, 2H), 3.85 (d, J = 11.0 Hz, 2H),3.69 (br. s., 6H), 3.30 (d, J = 11.0 Hz, 2H), 2.90 (br. s., 2H), 2.14(br. s., 2H), 2.03 (br. s., 1H), 1.65 (d, J = 12.8 Hz, 2H), 1.33 (d, J =10.1 Hz, 4H), 1.09 (d, J = 6.1 Hz, 2H), 0.67 (br. s., 3H) 1.56 A 470.4 B70

6-butyl-3- {5-[(3- chloro-4- fluoro- phenyl) methyl]- 1,3,4- oxadiazol-2-yl}-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.67 (br. s., 1H), 7.48- 7.39 (m, 2H), 7.35 (t, J = 7.8 Hz,1H), 6.73 (d, J = 7.6 Hz, 2H), 4.41 (br. s., 2H), 3.69 (br. s., 6H),2.15 (br. s., 2H), 1.33 (br. s., 2H), 1.09 (d, J = 5.8 Hz, 2H), 0.66(br. s., 3H) 1.98 A 514.3 A 71

6-butyl-3- {5-[(4- chloro-3- fluoro- phenyl) methyl]- 1,3,4- oxadiazol-2-yl}-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 11.72 (br. s., 2H), 7.60 (t, J = 8.1 Hz, 1H), 7.48 (dd, J =10.5, 1.9 Hz, 1H), 7.35 (t, J = 8.3 Hz, 1H), 7.26 (dd, J = 8.3, 1.7 Hz,1H), 6.72 (d, J = 8.5 Hz, 2H), 4.43 (s, 2H), 3.69 (s, 6H), 2.14 (t, J =7.3 Hz, 2H), 1.33 (quin, J = 7.6 Hz, 2H), 1.14-1.03 (m, 2H), 0.66 (t, J= 7.3 Hz, 3H) 1.08 D 514.1 A 72

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[2- (1,3-thiazol- 2-yl)ethyl]-1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ7.72 (br. s., 1H), 7.61 (br. s., 1H), 7.36 (t, J = 7.5 Hz, 1H), 6.73 (d,J = 7.6 Hz, 2H), 3.70 (br. s., 6H), 3.53 (br. s., 2H), 3.44 (br. s.,2H), 2.16 (br. s., 2H), 1.34 (br. s., 2H), 1.09 (d, J = 5.8 Hz, 2H),0.67 (br. s., 3H) 1.58 A 483.4 A 73

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-(5-{[3- (trifluoro- methyl)phenyl] methyl}- 1,3,4- oxadiazol- 2-yl) pyridine-2,4- diol 1H NMR (500MHz, DMSO-d6) δ 7.82 (br. s., 1H), 7.69 (br. s., 2H), 7.63 (d, J = 6.7Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 6.73 (d, J = 7.9 Hz, 2H), 4.52 (br.s., 2H), 3.69 (br. s., 6H), 2.14 (br. s., 2H), 1.33 (br. s., 2H), 1.09(d, J = 6.1 Hz, 2H), 0.66 (br. s., 3H) 2.01 A 530.2 B 74

6-butyl-3- {5-[2-(3,4- difluoro- phenyl) ethyl]- 1,3,4- oxadiazol-2-yl}-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.36 (t, J = 9.3 Hz, 1H), 7.32-7.21 (m, 2H), 7.09 (br. s.,1H), 6.67 (d, J = 7.6 Hz, 2H), 3.62 (br. s., 6H), 3.21 (br. s., 2H),3.04 (br. s., 2H), 2.09 (br. s., 2H), 1.27 (br. s., 2H), 1.02 (d, J =5.8 Hz, 2H), 0.59 (br. s., 3H) 1.99 A 512.4 A 75

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-(5-{2-[4- (trifluoro- methyl)phenyl] ethyl}- 1,3,4- oxadiazol- 2-yl) pyridine-2,4- diol 1H NMR (500MHz, DMSO-d6) δ 7.65 (d, J = 6.4 Hz, 2H), 7.54 (d, J = 6.4 Hz, 2H),7.39-7.30 (m, 1H), 6.73 (d, J = 7.3 Hz, 2H), 3.68 (br. s., 6H), 3.31(br. s., 2H), 3.20 (br. s., 2H), 2.15 (br. s., 2H), 1.33 (br. s., 2H),1.08 (d, J = 5.8 Hz, 2H), 0.65 (br. s., 3H) 2.12 A 544.3 B 76

6-butyl-3- [5-(3,4- difluoro- phenoxy- methyl)- 1,3,4- oxadiazol-2-yl]-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.44- 7.32 (m, 1H), 7.28 (br. s., 1H), 6.96 (br. s., 1H),6.72 (d, J = 7.6 Hz, 2H), 5.48 (br. s., 2H), 3.68 (br. s., 6H), 2.14(br. s., 2H), 1.33 (br. s., 2H), 1.08 (d, J = 4.9 Hz, 2H), 0.65 (br. s.,3H) 1.87 A 513.9 B 77

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[2- (3-phenyl- 1,2,4-oxadiazol- 5-yl) ethyl]-1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1HNMR (500 MHz, DMSO-d6) δ 7.98 (d, J = 4.0 Hz, 1H), 7.56 (d, J = 8.2 Hz,2H), 7.42-7.28 (m, 1H), 6.72 (d, J = 7.6 Hz, 2H), 3.67 (br. s., 6H),3.58- 3.37 (m, 4H), 2.14 (br. s., 2H), 1.32 (br. s., 2H), 1.08 (d, J =4.9 Hz, 2H), 0.65 (br. s., 3H) 1.92 A 544.3 B 78

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[(1- phenyl-1H- pyrazol-4-yl)methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 8.49 (br. s., 1H), 7.84- 7.75 (m, 3H), 7.49 (br. s., 2H),7.41- 7.25 (m, 2H), 6.73 (d, J = 7.6 Hz, 2H), 4.30 (br. s., 2H), 3.68(br. s., 6H), 2.15 (br. s., 2H), 1.32 (br. s., 2H), 1.09 (br. s., 2H),0.65 (br. s., 3H) 2.01 B 528.4 B 79

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[(2- methyl- l,3-thiazol-4-yl) methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500MHz, DMSO-d6) δ 11.72 (s, 1H), 7.43 (s, 1H), 7.36 (t, J = 8.4 Hz, 1H),6.73 (d, J = 8.5 Hz, 2H), 4.44 (s, 2H), 3.70 (s, 6H), 2.63 (s, 3H),2.19- 2.11 (m, 2H), 1.33 (dt, J = 15.1, 7.6 Hz, 2H), 1.14-1.05 (m, 2H),0.66 (t, J = 7.3 Hz, 3H) 1.90 C 483.1 A 80

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-(5-{[4- (trifluoro- methyl)phenyl] methyl}- 1,3,4- oxadiazol- 2-yl) pyridine-2,4- diol 1H NMR (500MHz, DMSO-d6) δ 7.74 (d, J = 6.1 Hz, 2H), 7.61 (br. s., 2H), 7.34 (br.s., 1H), 6.72 (d, J = 7.6 Hz, 2H), 4.48 (br. s., 2H), 3.67 (br. s., 6H),2.13 (br. s., 2H), 1.31 (br. s., 2H), 1.08 (br. s., 2H), 0.65 (br. s.,3H) 2.16 B 530.2 A 81

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[2- (pyrimidin- 2-yl)ethyl]-1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ8.73 (br. s., 2H), 7.36 (d, J = 4.0 Hz, 2H), 6.72 (d, J = 7.6 Hz, 2H),3.68 (br. s., 6H), 3.50 (d, J = 13.7 Hz, 2H), 3.44 (br. s., 2H), 2.15(br. s., 2H), 1.33 (br. s., 2H), 1.08 (d, J = 5.8 Hz, 2H), 0.65 (br. s.,3H) 1.43 A 477.9 A 82

3-{5-[2- (1,3-benzo- thiazol-2- yl)ethyl]- 1,3,4- oxadiazol- 2-yl}-6-butyl-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 11.75 (s, 1H), 8.07 (dd, J = 8.0, 0.5 Hz, 1H), 7.95 (d, J =7.4 Hz, 1H), 7.50 (td, J = 7.6, 1.2 Hz, 1H), 7.45-7.39 (m, 1H), 7.35 (t,J = 8.4 Hz, 1H), 6.73 (d, J = 8.5 Hz, 2H), 3.69 (s, 6H), 3.67 (t, J =6.9 Hz, 2H), 3.56 (t, J = 8.0 Hz, 2H), 2.20-2.11 (m, 2H), 1.39-1.30 (m,2H), 1.15-1.06 (m, 2H), 0.67 (t, J = 7.4 Hz, 3H) 2.07 C 533.2 A 83

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-(5-{2-[3- (pyridin- 2-yl)- 1,2,4-oxadiazol- 5-yl]ethyl}- 1,3,4- oxadiazol- 2-yl) pyridine-2,4- diol 1HNMR (500 MHz, DMSO-d6) δ 8.75 (br. s., 1H), 8.05 (br. s., 1H), 8.01 (br.s., 1H), 7.60 (br. s., 1H), 7.39-7.31 (m, 1H), 6.72 (d, J = 7.9 Hz, 2H),3.67 (br. s., 6H), 3.58 (br. s., 2H), 3.50 (d, J = 11.0 Hz, 2H), 2.15(br. s., 2H), 1.32 (br. s., 2H), 1.07 (br. s., 2H), 0.65 (br. s., 3H)1.65 A 545.2 A 84

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[(5- methyl-2- phenyl-1,3-thiazol-4- yl)methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR(500 MHz, DMSO-d6) δ 7.83 (br. s., 2H), 7.46 (br. s., 3H), 7.39-7.29 (m,1H), 6.72 (d, J = 7.9 Hz, 2H), 4.47 (br. s., 2H), 3.67 (br. s., 6H),2.55 (br. s., 3H), 2.14 (br. s., 2H), 1.32 (br. s., 2H), 1.07 (br. s.,2H), 0.64 (br. s., 3H) 2.19 B 559.2 A 85

6-butyl-3- {5-[2-(3,4- dichloro- phenyl) ethyl]- 1,3,4- oxadiazol-2-yl}-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.58 (br. s., 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.33-7.22 (m,2H), 6.66 (d, J = 7.9 Hz, 2H), 3.62 (br. s., 6H), 3.23 (br. s., 2H),3.05 (br. s., 2H), 2.08 (br. s., 2H), 1.27 (br. s., 2H), 1.02 (br. s.,2H), 0.59 (br. s., 3H) 2.16 A 544.3 B 86

3-[5-(1,2- benzoxazol- 3-ylmethyl)- 1,3,4- oxadiazol- 2-yl]-6- butyl-5-(2,6- dichloro- phenyl) pyridine-2,4- diol 1H NMR (400 MHz, CDCl3) δ12.26 (br. s., 1H), 7.81 (d, J = 7.9 Hz, 1H), 7.61- 7.54 (m, 2H), 7.50-7.43 (m, 2H), 7.37- 7.30 (m, 2H), 4.70 (s, 2H), 2.46-2.32 (m, 2H), 1.59(quin, J = 7.6 Hz, 2H), 1.34-1.20 (m, 2H), 0.77 (t, J = 7.3 Hz, 3H) 2.18C 511.0 A 87

6-butyl-3- {5-[(4- chloro- phenyl) methyl]- 1,3,4- oxadiazol- 2-yl}-5-(2,6- dichloro- phenyl) pyridine-2,4- diol 1H NMR (400 MHz, CDCl3) δ11.94 (br. s., 1H), 7.50-7.44 (m, 2H), 7.37-7.27 (m, 5H), 4.26 (s, 2H),2.43-2.34 (m, 2H), 1.62-1.52 (m, 2H), 1.32-1.20 (m, 2H), 0.79 (t, J =7.3 Hz, 3H) 2.29 C 506.0 B 88

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5- [(dimethyl- amino)(4- fluoro-phenyl) methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500MHz, DMSO-d6) δ 7.60- 7.50 (m, 2H), 7.35 (t, J = 8.2 Hz, 1H), 7.28-7.18(m, 2H), 6.73 (d, J = 8.2 Hz, 2H), 5.14 (br. s., 1H), 3.68 (br. s., 6H),2.23 (br. s., 6H), 2.15 (t, J = 7.5 Hz, 2H), 1.39- 1.28 (m, 2H), 1.15-1.03 (m, 2H), 0.66 (t, J = 7.2 Hz, 3H) 1.92 A 523.4 A 89

3-[5-(1,2- benzoxazol- 3-ylmethyl)- 1,3,4- oxadiazol- 2-yl]-5- (2,6-dimethoxy- phenyl)-6- (ethoxy- methyl) pyridine-2,4- diol 1H NMR (500MHz, DMSO-d6) δ 7.96 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.71(t, J = 7.6 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.37 (t, J = 8.4 Hz, 1H),6.73 (d, J = 8.2 Hz, 2H), 4.92 (s, 2H), 3.96 (s, 2H), 3.69 (s, 6H), 3.27(q, J = 6.8 Hz, 2H), 0.99 (t, J = 7.0 Hz, 3H) 1.41 A 505.3 A 90

3-{5-[(4- chloro- phenyl) methyl]- 1,3,4- oxadiazol- 2-yl}-5- (2,6-dimethoxy- phenyl)-6- (ethoxy- methyl) pyridine-2,4- diol 1H NMR (500MHz, DMSO-d6) δ 7.53- 7.29 (m, 5H), 6.74 (d, J = 8.5 Hz, 2H), 4.40 (s,2H), 3.96 (s, 2H), 3.69 (s, 6H), 3.27 (d, J = 7.0 Hz, 2H), 1.00 (t, J =7.0 Hz, 3H) 1.63 A 498.6 A 91

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[(5- methyl-2- phenyl-1,3-oxazol-4- yl)methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR(500 MHz, DMSO-d6) δ 7.92 (dd, J = 7.3, 2.3 Hz, 2H), 7.55-7.48 (m, 3H),7.36 (t, J = 8.4 Hz, 1H), 6.73 (d, J = 8.5 Hz, 2H), 4.32 (s, 2H), 3.69(s, 6H), 2.45 (s, 3H), 2.20-2.12 (m, 2H), 1.39-1.29 (m, 2H), 1.14-1.04(m, 2H), 0.66 (t, J = 7.4 Hz, 3H) 1.97 A 543.4 A 92

3-[5-(1,2- benzoxazol- 3-ylmethyl)- 1,3,4- oxadiazol- 2-yl]-6- cyclo-propyl-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.98 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.70 (t,J = 7.8 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H),6.74 (d, J = 8.5 Hz, 2H), 4.92 (s, 2H), 3.71 (s, 6H), 1.48 (br. s., 1H),0.98 (d, J = 4.9 Hz, 2H), 0.77 (d, J = 6.7 Hz, 2H) 1.60 A 486.9 B 93

3-{5-[(4- chloro- phenyl) methyl]- 1,3,4- oxadiazol- 2-yl}-6- cyclo-propyl-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.51- 7.29 (m, 5H), 6.74 (d, J = 8.5 Hz, 2H), 4.39 (s, 2H),3.71 (s, 6H), 1.47 (br. s., 1H), 0.97 (d, J = 4.3 Hz, 2H), 0.76 (d, J =6.4 Hz, 2H) 1.74 A 480.0 B 94

6-cyclo- propyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[(2- methyl-1,3-thiazol- 4-yl) methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol1H NMR (500 MHz, DMSO-d6) δ 7.43 (s, 1H), 7.36 (t, J = 8.2 Hz, 2H), 6.74(d, J = 8.2 Hz, 2H), 4.44 (s, 2H), 3.76- 3.65 (m, 6H), 2.63 (s, 3H),1.47 (d, J = 5.5 Hz, 1H), 0.97 (d, J = 4.6 Hz, 2H), 0.76 (d, J = 7.0 Hz,2H) 1.40 A 467.2 B 95

6-cyclo- propyl-5- (2,6- dimethoxy- phenyl)- 3-(5-{[3- (pyridin-2-yl)-1,2,4- oxadiazol- 5-yl] methyl}- 1,3,4- oxadiazol- 2-yl)pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ 8.77 (d, J = 4.6 Hz, 1H),8.08 (d, J = 7.6 Hz, 1H), 8.03 (t, J = 7.6 Hz, 1H), 7.70-7.49 (m, 1H),7.36 (t, J = 8.4 Hz, 1H), 6.75 (d, J = 8.5 Hz, 2H), 5.10 (s, 2H), 3.71(s, 6H), 1.47 (d, J = 5.5 Hz, 1H), 0.97 (d, J = 4.3 Hz, 2H), 0.77 (d, J= 6.7 Hz, 2H) 1.37 A 515.0 A 96

ethyl 2-{5- [6-butyl- 5-(2,6- dimethoxy- phenyl)- 2,4- dihydroxy-pyridin- 3-yl]-1,3,4- oxadiazol- 2-yl}acetate 1H NMR (500 MHz, DMSO-d6)δ 7.37 (t, J = 8.4 Hz, 1H), 6.74 (d, J = 8.2 Hz, 2H), 4.27 (s, 2H), 4.18(q, J = 7.0 Hz, 2H), 3.70 (s, 6H), 2.16 (t, J = 7.6 Hz, 2H), 1.39-1.29(m, 2H), 1.23 (t, J = 6.9 Hz, 3H), 1.17- 1.01 (m, 2H), 0.66 (t, J = 7.3Hz, 3H) 1.63 A 458.3 B 98

3-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]-1,3,4- oxadiazol- 2-yl} methyl)-1- methyl- imida- zolidine-2,4-dione 1H NMR (500 MHz, DMSO-d6) δ 7.34 (t, J = 8.2 Hz, 1H), 6.71 (d,J = 8.3 Hz, 2H), 4.89 (s, 2H), 4.10 (s, 2H), 3.68 (s, 6H), 2.89 (s, 3H),2.12 (t, J = 7.2 Hz, 2H), 1.40-1.24 (m, 2H), 1.14-0.99 (m, 2H), 0.65 (t,J = 7.3 Hz, 3H) 1.18 A 498.1 A 99

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[(3- fluoro- phenyl) methyl]-1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ7.41 (q, J = 7.3 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.26-7.17 (m, 2H),7.13 (t, J = 7.7 Hz, 1H), 6.72 (d, J = 8.4 Hz, 2H), 4.38 (s, 2H), 3.66(s, 6H), 2.13 (t, J = 7.6 Hz, 2H), 1.36- 1.24 (m, 2H), 1.12- 1.00 (m,2H), 0.63 (t, J = 7.3 Hz, 3H) 1.76 A 480.3 A 100

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-[5- (piperidin- 1-ylmethyl)-1,3,4- oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ7.36 (t, J = 8.3 Hz, 1H), 6.73 (d, J = 8.4 Hz, 2H), 3.74 (br. s., 6H),3.67 (br. s., 2H), 2.44 (br. s., 4H), 2.15 (br. s., 2H), 1.50 (br. s.,4H), 1.40-1.24 (m, 4H), 1.07 (d, J = 7.0 Hz, 2H), 0.64 (t, J = 7.2 Hz,3H) 1.57 A 469.1 B 101

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-(5-{[3- (pyridin-3- yl)-1,2,4-oxadiazol- 5-yl] methyl}- 1,3,4- oxadiazol- 2-yl) pyridine-2,4- diol 1HNMR (500 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.80 (d, J = 4.6 Hz, 1H), 8.38(d, J = 7.9 Hz, 1H), 7.63 (dd, J = 7.8, 5.0 Hz, 1H), 7.37 (t, J = 8.4Hz, 1H), 6.74 (d, J = 8.5 Hz, 2H), 5.11 (s, 2H), 3.70 (s, 6H), 2.16 (t,J = 7.5 Hz, 1H), 1.41-1.30 (m, 1H), 1.14-1.03 (m, 1H), 0.66 (t, J = 7.3Hz, 1H) 1.87 C 531.1 A 102

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[(1- methyl-1H- pyrazol- 4-yl)methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.68 (s, 1H), 7.42 (s, 1H), 7.36 (t, J = 8.3 Hz, 1H), 6.73(d, J = 8.3 Hz, 2H), 4.17 (s, 2H), 3.80 (s, 3H), 3.69 (s, 6H), 2.14 (t,J = 7.6 Hz, 2H), 1.40-1.27 (m, 2H), 1.14-1.00 (m, 2H), 0.66 (t, J = 7.3Hz, 3H) 1.34 A 466.1 C 103

6-butyl-3- {5-[(4- chloro-2- fluoro- phenyl) methyl]- 1,3,4- oxadiazol-2-yl}-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.58- 7.43 (m, 2H), 7.39- 7.23 (m, 2H), 6.72 (d, J = 8.4 Hz,2H), 4.38 (s, 2H), 3.67 (s, 6H), 2.13 (t, J = 7.5 Hz, 2H), 1.39- 1.25(m, 2H), 1.16- 0.97 (m, 2H), 0.64 (t, J = 7.3 Hz, 3H) 1.90 A 514.1 A 104

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-(5-{[3- (pyridin- 4-yl)-1,2,4-oxadiazol- 5-yl] methyl}- 1,3,4- oxadiazol- 2-yl) pyridine-2,4- diol 1HNMR (500 MHz, DMSO-d6) δ 8.81 (d, J = 4.6 Hz, 2H), 7.95 (d, J = 5.2 Hz,2H), 7.36 (t, J = 8.2 Hz, 1H), 6.74 (d, J = 8.2 Hz, 2H), 5.11 (s, 2H),3.70 (s, 6H), 2.16 (t, J = 7.6 Hz, 2H), 1.40-1.30 (m, 2H), 1.15-1.04 (m,2H), 0.66 (t, J = 7.2 Hz, 3H) 1.81 C 531.1 A 105

1-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]-1,3,4- oxadiazol- 2-yl} methyl) pyrrolidin- 2-one 1H NMR (500 MHz,DMSO-d6) δ 11.73 (br. s., 1H), 11.62 (br. s., 1H), 7.36 (t, J = 8.4 Hz,1H), 6.73 (d, J = 8.5 Hz, 2H), 4.75 (s, 2H), 3.70 (s, 6H), 3.47 (t, J =7.0 Hz, 2H), 2.30 (t, J = 8.1 Hz, 2H), 2.15 (t, J = 7.7 Hz, 2H),2.06-1.90 (m, 2H), 1.34 (dt, J = 15.1, 7.5 Hz, 2H), 1.16-1.01 (m, 2H),0.66 (t, J = 7.3 Hz, 3H) 1.80 C 469.0 A 106

5-(2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl)- 3-{5-[(2- methyl- 1,3-thiazol- 4-yl) methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1HNMR (500 MHz, DMSO-d6) δ 7.44 (s, 1H), 7.37 (t, J = 8.4 Hz, 1H), 6.74(d, J = 8.5 Hz, 2H), 4.44 (s, 2H), 3.95 (s, 2H), 3.70 (s, 6H), 3.28 (q,J = 7.0 Hz, 2H), 2.64 (s, 3H), 1.00 (t, J = 7.0 Hz, 3H) 1.25 A 485.2 A107

5-(2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl)- 3-(5-{[5- (pyridin-2-yl)- 1,2,4- oxadiazol- 3-yl] methyl}- 1,3,4- oxadiazol- 2-yl) 1H NMR(500 MHz, DMSO-d6) δ 8.78 (d, J = 4.3 Hz, 1H), 8.09 (d, J = 7.3 Hz, 1H),8.04 (t, J = 7.6 Hz, 1H), 7.69-7.57 (m, 1H), 7.38 (t, J = 8.2 Hz, 1H),6.74 (d, J = 8.5 Hz, 2H), 5.12 (s, 2H), 3.97 (s, 2H), 3.71 (s, 6H), 3.28(q, J = 7.0 Hz, 2H), 1.00 (t, J = 6.9 Hz, 3H) 1.21 A 533.0 Apyridine-2,4- diol 108

3-{5-[(3- benzyl- 1,2,4- oxadiazol- 5-yl) methyl]- 1,3,4- oxadiazol-2-yl}-6- butyl-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR(500 MHz, DMSO-d6) δ 7.38- 7.21 (m, 6H), 6.74 (d, J = 8.5 Hz, 2H), 4.95(s, 2H), 4.12 (s, 2H), 3.70 (s, 6H), 2.16 (t, J = 7.6 Hz, 2H), 1.34(quin, J = 7.4 Hz, 2H), 1.15-1.03 (m, 2H), 0.66 (t, J = 7.3 Hz, 3H) 2.12C 544.1 A 109

6-butyl-3- {5-[(3- cyclo- propyl- 1,2,4- oxadiazol- 5-yl) methyl]-1,3,4- oxadiazol- 2-yl}-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol1H NMR (500 MHz, DMSO-d6) δ 7.36 (t, J = 8.3 Hz, 1H), 6.74 (d, J = 8.5Hz, 3H), 4.91 (s, 2H), 3.70 (s, 6H), 2.20- 2.10 (m, 2H), 1.38- 1.29 (m,2H), 1.15- 1.03 (m, 4H), 0.94- 0.85 (m, 2H), 0.67 (t, J = 7.2 Hz, 3H).Methine peak obscured by solvent 2.00 C 494.0 A 110

3-{5-[(6- chloro- pyridin- 3-yl) methyl]- 1,3,4- oxadiazol- 2-yl}-5-(2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl) pyridine-2,4- diol 1H NMR(500 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.56 (d, J= 8.2 Hz, 1H), 7.37 (t, J = 8.2 Hz, 1H), 6.74 (d, J = 8.5 Hz, 2H), 4.48(s, 2H), 3.97 (s, 2H), 3.70 (s, 6H), 3.41-3.20 (m, 2H), 1.00 (t, J = 6.9Hz, 3H) 1.41 A 499.1 A 111

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-{5-[(3- phenyl- 1,2,4- oxadiazol-5-yl) methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500MHz, DMSO-d6) δ 8.03 (d, J = 8.0 Hz, 2H), 7.65-7.53 (m, 3H), 7.37 (t, J= 8.1 Hz, 1H), 6.74 (d, J = 8.3 Hz, 2H), 5.09 (s, 2H), 3.70 (s, 6H),2.16 (t, J = 7.7 Hz, 2H), 1.34 (quin, J = 7.2 Hz, 2H), 1.13-1.03 (m,2H), 0.67 (t, J = 7.2 Hz, 3H) 2.14 C 530.1 A 112

1-({5-[5- (2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl)- 2,4- dihydroxy-pyridin- 3-yl]-1,3,4- oxadiazol- 2-yl} methyl) pyrrolidin- 2-one 1H NMR(500 MHz, CDCl3) δ 7.38 (t, J = 8.4 Hz, 1H), 6.65 (d, J = 8.5 Hz, 2H),4.84 (s, 2H), 4.15 (s, 2H), 3.76 (s, 6H), 3.61 (t, J = 7.2 Hz, 2H), 3.53(q, J = 7.2 Hz, 2H), 2.47 (t, J = 8.1 Hz, 2H), 2.13 (quin, J = 7.6 Hz,2H), 1.24 (t, J = 7.0 Hz, 3H) 1.64 C 471.1 A 113

3-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]-1,3,4- oxadiazol- 2-yl} methyl) imida- zolidine- 2,4-dione 1H NMR(500 MHz, DMSO-d6) δ 7.36 (t, J = 8.4 Hz, 1H), 6.74 (d, J = 8.2 Hz, 2H),4.83 (s, 2H), 4.07 (s, 2H), 3.70 (s, 6H), 2.16 (t, J = 7.6 Hz, 2H),1.41- 1.29 (m, 2H), 1.14- 1.02 (m, 2H), 0.67 (t, J = 7.3 Hz, 3H) 1.30 A484.1 B 114

1-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl)- 1,2- dihydro- pyridin-2- one 1HNMR (500 MHz, DMSO-d6) δ 7.89- 7.80 (m, 1H), 7.52 (ddd, J = 9.0, 6.9,1.8 Hz, 1H), 7.36 (t, J = 8.4 Hz, 1H), 6.73 (d, J = 8.5 Hz, 2H), 6.46(d, J = 9.2 Hz, 1H), 6.35 (t, J = 6.1 Hz, 1H), 5.47 (s, 2H), 3.70 (s,6H), 2.16 (t, J = 7.8 Hz, 2H), 1.34 (quin, J = 7.5 Hz, 2H), 1.10 (sxt, J= 7.3 Hz, 2H), 0.67 (t, J = 7.3 Hz, 3H) 1.36 A 479.1 A 115

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-[5-(1H- imidazol- 1-ylmethyl)-1,3,4- oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ7.89 (s, 1H), 7.36 (t, J = 8.4 Hz, 1H), 7.32 (s, 1H), 7.01 (s, 1H), 6.74(d, J = 8.5 Hz, 2H), 5.73 (s, 2H), 3.70 (s, 6H), 2.16 (t, J = 7.6 Hz,2H), 1.34 (quin, J = 7.5 Hz, 2H), 1.15-1.05 (m, 2H), 0.67 (t, J = 7.3Hz, 3H) 1.33 A 452.2 B 116

3-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl)- 1,3- oxazolidin- 2-one 1H NMR(500 MHz, DMSO-d6) δ 7.36 (t, J = 8.4 Hz, 1H), 6.74 (d, J = 8.2 Hz, 2H),4.76 (s, 2H), 4.36 (t, J = 7.9 Hz, 2H), 3.73-3.66 (m, 8H), 2.15 (t, J =7.6 Hz, 2H), 1.40-1.29 (m, 2H), 1.15-1.06 (m, 2H), 0.67 (t, J = 7.2 Hz,3H) 1.39 A 471.3 A 117

4-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl) morpholin- 3-one 1H NMR (500 MHz,DMSO-d6) δ 7.36 (t, J = 8.4 Hz, 1H), 6.74 (d, J = 8.2 Hz, 2H), 4.92 (s,2H), 4.14 (s, 2H), 3.90 (t, J = 4.9 Hz, 2H), 3.70 (s, 6H), 3.54 (t, J =4.9 Hz, 2H), 2.16 (t, J = 7.5 Hz, 2H), 1.40-1.28 (m, 2H), 1.16-1.04 (m,2H), 0.67 (t, J = 7.3 Hz, 3H) 1.37 A 485.4 A 118

tert-butyl 2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy-pyridin- 3-yl]- 1,3,4- oxadiazol- 2-yl} acetate 1H NMR (500 MHz,DMSO-d6) δ 7.37 (t, J = 8.3 Hz, 1H), 6.74 (d, J = 8.5 Hz, 2H), 4.16 (s,2H), 3.70 (s, 6H), 2.16 (t, J = 7.6 Hz, 2H), 1.45 (s, 9H), 1.37- 1.27(m, 2H), 1.15- 1.02 (m, 2H), 0.67 (t, J = 7.3 Hz, 3H) 2.07 C 486.2 A 119

1-({5-[5- (2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl)- 2,4- dihydroxy-pyridin- 3-yl]-1,3,4- oxadiazol- 2-yl} methyl)- 1,2- dihydro- pyridin-2-one 1H NMR (500 MHz, DMSO-d6) δ 7.85 (d, J = 6.7 Hz, 1H), 7.52 (t, J =7.8 Hz, 1H), 7.36 (t, J = 8.2 Hz, 1H), 6.73 (d, J = 8.5 Hz, 2H), 6.47(d, J = 9.2 Hz, 1H), 6.35 (t, J = 6.6 Hz, 1H), 5.47 (s, 2H), 3.96 (s,2H), 3.70 (s, 6H), 3.29 (q, J = 6.7 Hz, 2H), 1.01 (t, J = 6.9 Hz, 3H)1.61 A 481.1 A 120

tert-butyl N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy-pyridin- 3-yl]- 1,3,4- oxadiazol- 2-yl} methyl) carbamate 1H NMR (500MHz, CDCl3) δ 7.39 (t, J = 8.4 Hz, 1H), 6.68 (d, J = 8.5 Hz, 2H), 4.69(d, J = 5.8 Hz, 2H), 3.78 (s, 6H), 2.34 (t, J = 7.7 Hz, 2H), 1.53- 1.45(m, 9H), 1.37- 1.18 (m, 4H), 0.82 (t, J = 7.4 Hz, 3H). 2.03 C 501.1 B121

tert-butyl N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy-pyridin- 3-yl]- 1,3,4- oxadiazol- 1H NMR (500 MHz, CDCl3) δ 7.39 (t, J =8.3 Hz, 1H), 6.68 (d, J = 8.5 Hz, 2H), 4.84-4.64 (m, 2H), 3.78 (s, 6H),3.06 (br. s., 3H), 2.35 (t, J = 7.7 Hz, 2H), 1.55-1.41 (m, 11H),1.33-1.19 (m, 2H), 0.81 (t, J = 7.4 Hz, 3H) 2.09 C 515.2 B 2-yl}methyl)-N- methyl- carbamate 122

3-{5-[(4- chloro-3- fluoro- phenyl) methyl]- 1,3,4- oxadiazol- 2-yl}-5-(2,6- dimethoxy- phenyl)-6- (ethoxy- methyl) pyridine-2,4- diol 1H NMR(500 MHz, DMSO-d6) δ 7.59 (t, J = 8.1 Hz, 1H), 7.47 (d, J = 10.4 Hz,1H), 7.35 (t, J = 8.4 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 6.72 (d, J =8.2 Hz, 2H), 4.43 (s, 2H), 3.95 (s, 2H), 3.68 (s, 6H), 3.26 (q, J = 6.9Hz, 2H), 0.98 (t, J = 6.9 Hz, 3H) 1.71 A 516.3 A 123

3-{5-[(4- chloro-2- fluoro- phenyl) methyl]- 1,3,4- oxadiazol- 2-yl}-5-(2,6- dimethoxy- phenyl)-6- (ethoxy- methyl) pyridine-2,4- diol 1H NMR(500 MHz, DMSO-d6) δ 11.76 (br. s., 1H), 11.44 (br. s., 1H), 7.57- 7.45(m, 2H), 7.39- 7.26 (m, 2H), 6.79- 6.67 (m, 2H), 4.41 (s, 2H), 3.94 (s,2H), 3.68 (s, 6H), 3.29-3.21 (m, 2H), 0.98 (t, J = 6.9 Hz, 3H) 1.70 A516.0 A 124

5-(2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl)- 3-{5-[(5- fluoro-pyridin- 2-yl) methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1HNMR (500 MHz, DMSO-d6) δ 11.92 (br. s., 1H), 11.45 (br. s., 1H), 8.51(d, J = 3.0 Hz, 1H), 7.78 (td, J = 8.7, 3.0 Hz, 1H), 7.59 (dd, J = 8.5,4.4 Hz, 1H), 7.37 (t, J = 8.4 Hz, 1H), 6.73 (d, J = 8.5 Hz, 2H), 4.58(s, 2H), 3.95 (s, 2H), 3.27 (q, J = 6.9 Hz, 2H), 0.99 (t, J = 6.9 Hz,3H) 0.84 D 483.1 A 125

5-(2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl)- 3-[5-(1H- imidazol-1-ylmethyl)- 1,3,4- oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.86 (br. s., 1H), 7.38 (s, 1H), 7.31 (br. s., 1H), 7.00 (br.s., 1H), 6.74 (d, J = 8.2 Hz, 2H), 5.73 (s, 2H), 3.97 (s, 2H), 3.36 (br.s., 4H), 3.30 (br. s., 2H), 3.29-3.11 (m, 2H), 1.00 (t, J = 6.9 Hz, 3H)1.12 A 454.3 B 126

5-(2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl)- 3-{5-[(3- fluoro-4-methyl- phenyl) methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1HNMR (500 MHz, DMSO-d6) δ 7.42- 7.02 (m, 4H), 6.68 (d, J = 8.5 Hz, 2H),4.32 (s, 2H), 3.91 (s, 2H), 3.39 (br. s., 6H), 3.22 (q, J = 7.0 Hz, 2H),2.18 (s, 3H), 0.94 (t, J = 6.7 Hz, 3H) 1.78 A 496.2 A 127

3-{5-[(5- chloro- pyridin- 2-yl) methyl]- 1,3,4- oxadiazol- 2-yl}-5-(2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl) pyridine-2,4- diol 1H NMR(500 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.99 (d, J = 8.5 Hz, 1H), 7.57 (d, J= 8.2 Hz, 1H), 7.38 (t, J = 8.4 Hz, 1H), 6.74 (d, J = 8.2 Hz, 2H), 4.60(s, 2H), 3.96 (s, 2H), 3.71 (s, 6H), 3.37-3.14 (m, 2H), 1.00 (t, J = 6.9Hz, 3H) 1.46 A 499.0 A 128

5-(2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl)- 3-{5-[(3- phenyl- 1H-pyrazol- 1-yl) methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1HNMR (500 MHz, DMSO-d6) δ 8.01 (br. s., 1H), 7.87- 7.70 (m, J = 7.3 Hz,2H), 7.45-7.25 (m, 4H), 6.84 (br. s., 1H), 6.78-6.63 (m, J = 7.9 Hz,2H), 5.85 (br. s., 2H), 3.95 (s, 2H), 3.69 (s, 6H), 3.38-3.14 (m, 1H),2.56 (s, 1H), 0.99 (t, J = 6.7 Hz, 3H) 1.62 A 530.3 A 129

5-(2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl)- 3-(5-{[3- (trifluoro-methyl)- 1H- pyrazol- 1-yl] methyl}- 1,3,4- oxadiazol- 2-yl)pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ 8.20 (br. s., 1H), 7.36(br. s., 1H), 6.86 (br. s., 1H), 6.73 (d, J = 8.2 Hz, 2H), 5.96 (s, 2H),3.95 (s, 2H), 3.45-3.21 (m, 8H), 1.00 (t, J = 6.7 Hz, 3H) 1.54 A 522.2 B130

5-(2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl)- 3-{5-[(1- methyl- 1H-pyrazol- 4-yl) methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1HNMR (500 MHz, DMSO-d6) δ 7.69 (s, 1H), 7.42 (s, 1H), 7.35 (t, J = 7.8Hz, 1H), 6.72 (d, J = 8.2 Hz, 2H), 4.17 (br. s., 2H), 3.94 (s, 2H), 3.82(s, 3H), 3.69 (s, 6H), 3.28 (d, J = 7.0 Hz, 2H), 1.01 (t, J = 6.7 Hz,3H) 1.30 A 468.3 B 131

5-(2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl)- 3-{5-[(6- fluoro-pyridin- 3-yl) methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1HNMR (500 MHz, DMSO-d6) δ 8.31 (br. s., 1H), 8.04 (t, J = 7.9 Hz, 1H),7.37 (t, J = 8.2 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 6.74 (d, J = 8.2 Hz,2H), 4.47 (s, 2H), 3.96 (s, 2H), 3.36 (br. s., 3H), 3.28 (q, J = 6.7 Hz,3H), 1.00 (t, J = 6.7 Hz, 3H) 1.32 A 483.2 A 132

5-(2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl)- 3-[5-(1H- indazol-3-ylmethyl)- 1,3,4- oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.75 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 8.2 Hz, 1H), 7.40-7.24(m, 2H), 7.07 (t, J = 7.0 Hz, 1H), 6.66 (d, J = 7.9 Hz, 2H), 4.63 (br.s., 2H), 3.87 (br. s., 2H), 3.63 (s, 6H), 3.21 (d, J = 6.7 Hz, 2H), 0.94(t, J = 6.7 Hz, 3H) 1.50 A 504.3 A 133

3-[5-(1H- 1,2,3- benzo- triazol-1- ylmethyl)- 1,3,4- oxadiazol- 2-yl]-5-(2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl) pyridine-2,4- diol 1H NMR(500 MHz, DMSO-d6) δ 8.11 (d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H),7.61 (t, J = 7.6 Hz, 1H), 7.46 (t, J = 7.5 Hz, 1H), 7.34 (t, J = 8.2 Hz,1H), 6.71 (d, J = 8.2 Hz, 2H), 6.50 (s, 2H), 3.93 (s, 2H), 3.67 (s, 6H),3.25 (q, J = 6.5 Hz, 2H), 0.98 (t, J = 6.9 Hz, 3H) 1.32 A 505.2 A 134

5-(2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl)- 3-[5-(1H- indazol-1-ylmethyl)- 1,3,4- oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 8.17 (s, 1H), 7.80 (t, J = 8.7 Hz, 2H), 7.45 (t, J = 7.5 Hz,1H), 7.34 (t, J = 8.1 Hz, 1H), 7.20 (t, J = 7.3 Hz, 1H), 6.71 (d, J =7.9 Hz, 2H), 6.10 (s, 2H), 3.93 (s, 2H), 3.67 (s, 6H), 3.25 (q, J = 6.3Hz, 2H), 0.97 (t, J = 6.6 Hz, 3H) 1.43 A 504.0 A 135

5-(2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl)- 3-{5-[(4- fluoro-phenyl) methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500MHz, DMSO-d6) δ 7.52- 7.30 (m, 3H), 7.19 (t, J = 8.2 Hz, 2H), 6.71 (d, J= 8.2 Hz, 2H), 4.36 (s, 2H), 3.93 (s, 2H), 3.68 (s, 6H), 3.26 (q, J =6.6 Hz, 2H), 0.98 (t, J = 6.6 Hz, 3H) 1.78 A 482.0 A 136

5-(2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl)- 3-[5-(1H- indol-1-ylmethyl)- 1,3,4- oxadiazol- 2-yl] pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.65- 6.94 (m, 6H), 6.67 (d, J = 8.5 Hz, 2H), 6.49 (d, J =3.1 Hz, 1H), 5.96-5.73 (m, 2H), 3.89 (s, 2H), 3.68-3.58 (s, 6H), 3.21(q, J = 6.8 Hz, 2H), 0.94 (t, J = 6.9 Hz, 3H) 1.75 A 503.3 B 138

3-[5-(1,2- benzoxazol- 3-ylmethyl)- 1,3,4- oxadiazol- 2-yl]-6- butyl-5-phenyl- pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ 7.96 (d, J = 7.9Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 7.48-7.34(m, 4H), 7.27 (d, J = 7.0 Hz, 2H), 4.93 (s, 2H), 2.37- 2.26 (m, 2H),1.41 (quin, J = 7.5 Hz, 2H), 1.11 (sxt, J = 7.3 Hz, 2H), 0.68 (t, J =7.3 Hz, 3H) 2.17 C 443.1 B 139

6-butyl-3- {5-[(3,4- difluoro- phenyl) methyl]- 1,3,4- oxadiazol-2-yl}-5- (3-methoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.55- 6.72 (m, 9H), 4.45- 4.30 (m, 2H), 4.35 (s, 2H), 3.71(s, 3H), 3.59-3.58 (m, 1H), 2.26 (t, J = 7.6 Hz, 2H), 2.35- 2.18 (m,2H), 1.44- 1.32 (m, 2H), 1.49- 1.31 (m, 2H), 1.13- 0.99 (m, 2H), 1.12-0.99 (m, 2H), 0.74- 0.56 (m, 3H), 0.65 (t, J = 7.3 Hz, 3H) 1.83 A 468.1B 140

6-butyl-3- {5-[(3,4- difluoro- phenyl) methyl]- 1,3,4- oxadiazol-2-yl}-5- (3-ethyl- phenyl) pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6)δ 7.59- 6.92 (m, 7H), 4.39 (s, 2H), 2.62 (q, J = 7.3 Hz, 2H), 2.28 (br.s., 2H), 1.58- 1.33 (m, 2H), 1.18 (t, J = 7.5 Hz, 3H), 1.14-0.92 (m,2H), 0.67 (t, J = 7.2 Hz, 3H) 2.11 A 466.0 B 141

6-butyl-3- {5-[(3,4- difluoro- phenyl) methyl]- 1,3,4- oxadiazol-2-yl}-5- [3-(trifluoro- methoxy) phenyl] pyridine-2,4- diol 1H NMR (500MHz, DMSO-d6) δ 7.72- 7.16 (m, 7H), 4.39 (s, 2H), 2.39-2.21 (m, 2H),1.52-1.31 (m, 2H), 1.19-1.00 (m, 2H), 0.66 (t, J = 7.3 Hz, 3H) 1.13 D522.2 B 142

5-[3- (benzyloxy) phenyl]- 6-butyl-3- {5-[(3,4- difluoro- phenyl)methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.61- 6.77 (m, 12H), 5.11 (s, 2H), 4.40 (s, 2H), 2.27 (t, J =7.6 Hz, 2H), 1.50-1.33 (m, 2H), 1.17-1.00 (m, 2H), 0.67 (t, J = 7.3 Hz,3H) 2.29 A 544.0 B 143

6-butyl-3- {5-[(3,4- difluoro- phenyl) methyl]- 1,3,4- oxadiazol-2-yl}-5- [3-(hydroxy- methyl) phenyl] pyridine-2,4- diol 1H NMR (500MHz, DMSO-d6) δ 7.55- 7.07 (m, 7H), 4.52 (d, J = 5.5 Hz, 2H), 4.40 (s,2H), 2.29 (t, J = 7.6 Hz, 2H), 1.50-1.35 (m, 2H), 1.18-1.02 (m, 2H),0.69 (t, J = 7.3 Hz, 3H) 1.53 A 468.0 A 144

6-butyl-5- (cyclohex- 1-en-1- yl)-3-{5- [(3,4- difluoro- phenyl)methyl]- 1,3,4- oxadiazol- 2-yl} pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.45 (td, J = 19.0, 9.0 Hz, 2H), 7.23 (br. s., 1H), 5.58 (br.s., 1H), 4.39 (s, 2H), 2.46-2.17 (m, 3H), 2.10 (br. s., 2H), 1.86 (br.s., 1H), 1.75-1.43 (m, 6H), 1.39-1.19 (m, 2H), 0.87 (t, J = 7.3 Hz, 3H)2.36 A 442.0 B 145

6-butyl-3- {5-[(3,4- difluoro- phenyl) methyl]- 1,3,4- oxadiazol-2-yl}-5- [3-(propan- 2-yl) phenyl] pyridine-2,4- diol 1H NMR (500 MHz,DMSO-d6) δ 7.51- 6.98 (m, 7H), 4.37 (s, 2H), 2.89 (dt, J = 13.7, 6.9 Hz,1H), 2.26 (br. s., 2H), 1.39 (quin, J = 7.5 Hz, 2H), 1.18 (d, J = 7.0Hz, 6H), 1.13-0.97 (m, 2H), 0.64 (t, J = 7.3 Hz, 3H) 2.42 A 480.1 B 146

6-butyl-3- {5-[(3,4- difluoro- phenyl) methyl]- 1,3,4- oxadiazol-2-yl}-5-[3- (methoxy- methyl) phenyl] pyridine-2,4- diol 1H NMR (500MHz, DMSO-d6) δ 7.55- 7.10 (m, 7H), 4.43 (s, 2H), 4.38 (s, 2H), 2.54 (s,3H), 2.27 (t, J = 7.6 Hz, 2H), 1.48-1.34 (m, 2H), 1.17-1.02 (m, 2H),0.68 (t, J = 7.3 Hz, 3H) 1.95 A 482.1 B 147

3-(2-butyl- 5-{5-[(3,4- difluoro- phenyl) methyl]- 1,3,4- oxadiazol-2-yl}-4,6- dihydroxy- pyridin- 3-yl)-N- (propan- 2-yl) benzamide 1H NMR(500 MHz, DMSO-d6) δ 8.29- 7.17 (m, 8H), 4.31 (s, 2H), 4.15-4.00 (m,1H), 2.20 (t, J = 7.5 Hz, 2H), 1.51-1.34 (m, 2H), 1.21-1.02 (m, 8H),0.68 (t, J = 7.3 Hz, 3H) 1.54 A 522.9 B 148

6-butyl-4- hydroxy- 3-{5-[(2- methyl- 1,3- thiazol- 4-yl) methyl]-1,3,4- oxadiazol- 2-yl}-5- [3-(propan- 2-yl) phenyl]- 1,2- dihydro-pyridin-2- one 1H NMR (500 MHz, DMSO-d6) δ 7.65- 7.18 (m, 3H), 7.17-6.98 (m, 2H), 4.44 (s, 2H), 3.07-2.83 (m, 1H), 2.62 (s, 3H), 2.27 (br.s., 2H), 1.50-1.35 (m, 2H), 1.21 (d, J = 6.7 Hz, 6H), 1.16- 1.03 (m,2H), 0.67 (t, J = 6.9 Hz, 3H) 2.09 A 465.3 A 149

3-(2-butyl- 4- hydroxy- 5-{5-[(2- methyl- 1,3- thiazol- 4-yl) methyl]-1,3,4- oxadiazol- 2-yl}-6- oxo-1,6- dihydro- pyridin- 3-yl)-N- (propan-1H NMR (500 MHz, DMSO-d6) δ 8.22 (d, J = 7.6 Hz, 1H), 7.92-7.65 (m, 2H),7.55-7.28 (m, 3H), 4.41 (s, 2H), 4.20- 4.04 (m, 1H), 2.62 (s, 3H), 2.25(d, J = 7.0 Hz, 2H), 1.51-1.32 (m, 2H), 1.21-1.00 (m, 8H), 0.67 (t, J =7.2 Hz, 3H) 1.32 A 508.0 A 2-yl) benzamide 150

6-butyl-5- (3-cyclo- propyl- phenyl)- 4-hydroxy- 3-{5-[(2- methyl- 1,3-thiazol- 4-yl) methyl]- 1,3,4- oxadiazol- 2-yl}-1,2- dihydro- pyridin-2-one 1H NMR (500 MHz, DMSO-d6) δ 7.42 (s, 1H), 7.29 (t, J = 7.5 Hz,1H), 7.10- 6.86 (m, 3H), 4.44 (s, 2H), 2.62 (s, 3H), 2.28 (t, J = 7.3Hz, 2H), 1.93 (br. s., 1H), 1.49- 1.35 (m, 2H), 1.17- 1.03 (m, 2H), 0.95(d, J = 7.9 Hz, 2H), 0.68 (t, J = 7.2 Hz, 5H) 1.99 A 463.3 A 151

6-butyl-4- hydroxy- 5-(3- methoxy- phenyl)- 3-{5-[(2- methyl- 1,3-thiazol- 4-yl) methyl]- 1,3,4- oxadiazol- 2-yl}-1,2- dihydro- pyridin-2-one 1H NMR (500 MHz, DMSO-d6) δ 7.47- 7.25 (m, 2H), 6.93 (d, J = 8.5Hz, 1H), 6.86-6.67 (m, 2H), 4.40 (s, 2H), 3.74 (s, 3H), 2.60 (s, 3H),2.29 (t, J = 7.6 Hz, 2H), 1.40 (quin, J = 7.5 Hz, 2H), 1.16-1.00 (m,2H), 0.67 (t, J = 7.3 Hz, 3H) 1.64 A 453.1 A 152

6-butyl-4- hydroxy- 5-[3- (hydroxy- methyl) phenyl]- 3-{5-[(2- methyl-1,3- thiazol- 4-yl) methyl]- 1,3,4- oxadiazol- 2-yl}-1,2- dihydro-pyridin- 2-one 1H NMR (500 MHz, DMSO-d6) δ 7.50- 7.26 (m, 3H), 7.23-6.94 (m, 2H), 4.52 (br. s., 2H), 4.44 (s, 2H), 2.62 (s, 3H), 2.29 (t, J= 7.3 Hz, 2H), 1.62-1.30 (m, 2H), 1.18-1.01 (m, 2H), 0.69 (t, J = 7.2Hz, 3H) 1.24 A 453.0 B 153

6-butyl-4- hydroxy- 3-{5-[(2- methyl- 1,3- thiazol- 4-yl) methyl]-1,3,4- oxadiazol- 2-yl}-5-[3- (pyrrolidin- 1-yl) phenyl]- 1,2- dihydro-pyridin-2- one 1H NMR (500 MHz, DMSO-d6) δ 7.42 (s, 1H), 7.19 (t, J =7.8 Hz, 1H), 6.68- 6.19 (m, 3H), 4.43 (s, 2H), 3.20 (br. s., 4H), 2.62(s, 3H), 2.31 (d, J = 7.0 Hz, 2H), 1.94 (br. s., 4H), 1.44 (d, J = 6.7Hz, 2H), 1.19- 1.03 (m, 2H), 0.71 (t, J = 7.3 Hz, 3H) 2.11 A 492.3 B 156

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]-1,3,4- oxadiazol- 2-yl} methyl)- 3-chloro- N-methyl- benzamide 1HNMR (500 MHz, DMSO-d6) δ 7.64- 7.47 (m, 4H), 7.35 (t, J = 8.4 Hz, 1H),6.73 (d, J = 8.3 Hz, 2H), 5.02 (br. s., 2H), 3.70 (s, 6H), 3.05 (br. s.,3H), 2.14 (t, J = 7.4 Hz, 2H), 1.40-1.27 (m, 2H), 1.14-1.02 (m, 2H),0.67 (t, J = 7.2 Hz, 3H) 0.96 D 553.3 A 157

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]-1,3,4- oxadiazol- 2-yl} methyl)- N-methyl- pyridine-2- carboxamide1H NMR (500 MHz, DMSO-d6) δ 8.66- 8.54 (m, 1H), 7.95 (dt, J = 15.1, 7.5Hz, 1H), 7.82-7.62 (m, 1H), 7.53 (dd, J = 13.3, 7.0 Hz, 1H), 7.36 (t, J= 8.4 Hz, 1H), 6.74 (d, J = 8.5 Hz, 2H), 5.07 (d, J = 15.1 Hz, 2H), 3.70(d, J = 4.7 Hz, 6H), 3.14 (d, J = 9.6 Hz, 3H), 2.16 (br. s., 2H), 1.34(d, J = 8.0 Hz, 2H), 1.10 (br. s., 2H), 0.67 0.84 D 520.4 A (t, J = 6.9Hz, 3H) 158

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl)-2- methoxy- acetamide 1H NMR (500MHz, DMSO-d6) δ 8.64 (t, J = 5.8 Hz, 1H), 7.36 (t, J = 8.3 Hz, 1H), 6.74(d, J = 8.3 Hz, 2H), 4.61 (d, J = 5.8 Hz, 2H), 3.91 (s, 2H), 3.70 (s,6H), 2.57-2.47 (m, 3H), 2.15 (t, J = 7.6 Hz, 2H), 1.41-1.27 (m, 2H),1.15-1.03 (m, 2H), 0.67 (t, J = 7.4 Hz, 3H) 0.81 D 473.4 A 159

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl)- N-methyl- pyridine-4-carboxamide 1H NMR (500 MHz, DMSO-d6) δ 8.78- 8.62 (m, 2H), 7.62 (br.s., 1H), 7.49 (br. s., 1H), 7.31 (br. s., 1H), 6.70 (d, J = 8.3 Hz, 2H),5.00 (br. s., 1H), 4.67 (br. s., 1H), 3.68 (s, 6H), 3.03 (d, J = 10.5Hz, 3H), 2.09 (br. s., 2H), 1.38-1.25 (m, 2H), 1.13-1.00 (m, 2H), 0.67(t, J = 7.3 Hz, 3H) 0.76 D 520.4 A 160

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl) pyridine-3- carboxamide 1H NMR(500 MHz, DMSO-d6) δ 9.66- 9.50 (m, 1H), 9.07 (s, 1H), 8.76 (d, J = 4.4Hz, 1H), 8.26 (d, J = 7.4 Hz, 1H), 7.63-7.48 (m, 1H), 7.35 (t, J = 8.3Hz, 1H), 6.73 (d, J = 8.0 Hz, 2H), 4.82 (d, J = 5.5 Hz, 2H), 3.70 (s,6H), 2.15 (t, J = 1.1 Hz, 2H), 1.40-1.27 (m, 2H), 1.14-1.02 (m, 2H),0.66 (t, J = 7.3 Hz, 3H) 0.76 D 506.4 A 161

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl)- 2-chloro- N-methyl- benzamide 1HNMR (500 MHz, DMSO-d6) δ 7.73- 7.31 (m, 5H), 6.75 (d, J = 8.3 Hz, 2H),5.08 (br. s., 2H), 3.74-3.63 (m, 6H), 3.05 (br. s., 3H2.93 (s, 2H), 2.17(t, J = 7.4 Hz, 2H), 1.35 (d, J = 6.9 Hz, 2H), 1.15-1.03 (m, 2H), 0.67(t, J = 7.3 Hz, 3H) 0.94 D 553.3 A 162

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl)- 3-chloro- benzamide 1H NMR (400MHz, DMSO-d6) δ 7.94 (t, J = 1.8 Hz, 1H), 7.86 (d, J = 7.7 Hz, 1H),7.70-7.64 (m, 1H), 7.60-7.47 (m, 1H), 7.34 (t, J = 8.4 Hz, 1H), 6.72 (d,J = 8.6 Hz, 2H), 4.78 (d, J = 5.5 Hz, 2H), 3.69 (s, 6H), 2.14 (t, J =7.5 Hz, 2H), 1.35-1.27 (m, 2H), 1.13-1.02 (m, 2H), 0.65 (t, J = 7.4 Hz,3H) 2.10 C 539.1 A 163

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl)- 4-chloro- benzamide 1H NMR (500MHz, DMSO-d6) δ 7.93 (d, J = 7.7 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.36(t, J = 8.4 Hz, 1H), 6.73 (d, J = 8.3 Hz, 2H), 4.79 (d, J = 5.0 Hz, 2H),3.70 (s, 6H), 2.15 (t, J = 7.6 Hz, 2H), 1.40-1.26 (m, 2H), 1.13-1.03 (m,2H), 0.67 (t, J = 7.2 Hz, 3H) 0.94 D 539.3 A 164

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl) pyridine-4- carboxamide 1H NMR(500 MHz, DMSO-d6) δ 8.77 (d, J = 5.0 Hz, 2H), 7.81 (d, J = 5.0 Hz, 2H),7.36 (t, J = 8.4 Hz, 1H), 6.74 (d, J = 8.3 Hz, 2H), 4.82 (d, J = 5.5 Hz,2H), 3.70 (s, 6H), 2.16 (t, J = 7.6 Hz, 2H), 1.39-1.28 (m, 2H),1.13-1.04 (m, 2H), 0.66 (t, J = 7.3 Hz, 3H) 0.75 D 506.4 A 165

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl)- N-methyl- pyridine-3-carboxamide 1H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J = 15.4 Hz, 2H),8.14-7.88 (m, 1H), 7.51 (br. s., 1H), 7.30 (br. s., 1H), 6.69 (d, J =8.5 Hz, 2H), 5.00 (br. s., 2H), 3.68 (s, 6H), (d, J = 10.5 Hz, 3H), 2.09(br. s., 2H), 1.44-1.27 (m, 2H), 1.15-0.98 (m, 2H), 0.67 (t, J = 7.3 Hz,3H) 0.77 D 520.4 A 166

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl)- 2-phenyl- acetamide 1H NMR (500MHz, DMSO-d6) δ 7.37- 7.29 (m, 5H), 7.23 (d, J = 3.9 Hz, 1H), 6.72 (d, J= 8.5 Hz, 2H), 4.59 (d, J = 5.5 Hz, 2H), 3.69 (s, 6H), 3.53 (s, 2H),2.14 (t, J = 7.6 Hz, 2H), 1.34 (t, J = 7.4 Hz, 2H), 1.16-1.04 (m, 2H),0.67 (t, J = 7.3 Hz, 3H) 0.91 D 519.4 A 167

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl)- 2,2- dimethyl- propan- amide 1HNMR (500 MHz, DMSO-d6) δ 9.54 (t, J = 5.8 Hz, 1H), 8.71 (d, J = 4.4 Hz,1H), 8.12-7.98 (m, 2H), 7.67 (d, J = 4.7 Hz, 1H), 7.36 (t, J = 8.5 Hz,1H), 6.74 (d, J = 8.3 Hz, 2H), 4.82 (d, J = 5.8 Hz, 2H), 3.70 (s, 6H),2.24-2.06 (m, 2H), 1.41-1.30 (m, 2H), 1.13-1.02 (m, 2H), 0.67 (t, J =7.3 Hz, 3H) 0.88 D 485.5 A 168

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl) pyridine-2- carboxamide 1H NMR(500 MHz, DMSO-d6) δ 9.54 (t, J = 5.8 Hz, 1H), 8.71 (d, J = 4.4 Hz, 1H),8.12-7.98 (m, 2H), 7.67 (d, J = 4.7 Hz, 1H), 7.36 (t, J = 8.5 Hz, 1H),6.74 (d, J = 8.3 Hz, 2H), 4.82 (d, J = 5.8 Hz, 2H), 3.70 (s, 6H),2.24-2.06 (m, 2H), 1.41-1.30 (m, 2H), 1.13-1.02 (m, 2H), 0.67 (t, J =7.3 Hz, 3H) 0.86 D 506.4 A 169

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl)- N,2,2- trimethyl- propan- amide1H NMR (500 MHz, DMSO-d6) δ 7.34- 7.25 (m, 1H), 6.68 (d, J = 8.3 Hz,2H), 4.79 (br. s., 2H), 3.67 (s, 6H), 2.56 (s, 3H), 2.06 (br. s., 2H),1.36-1.29 (m, 2H), 1.25 (s, 9H), 1.14-1.02 (m, 2H), 0.66 (t, J = 7.4 Hz,3H) 2.03 C 499.2 A 170

3-[5- (amino- methyl)- 1,3,4- oxadiazol- 2-yl]-6- butyl-5- (2,6-dimethoxy- phenyl) pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6) δ 7.36(t, J = 8.5 Hz, 1H), 6.74 (d, J = 8.0 Hz, 2H), 3.99 (s, 2H), 3.70 (s,6H), 2.15 (t, J = 7.6 Hz, 2H), 1.41-1.29 (m, 2H), 1.14-1.01 (m, 2H),0.67 (t, J = 7.0 Hz, 3H) 1.60 C 401.1 B 171

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl) benzamide 1H NMR (500 MHz,DMSO-d6) δ 7.91 (d, J = 7.4 Hz, 2H), 7.61-7.56 (m, 1H), 7.54-7.46 (m,2H), 7.36 (t, J = 8.4 Hz, 1H), 6.73 (d, J = 8.5 Hz, 2H), 4.78 (d, J =5.2 Hz, 2H), 3.69 (s, 6H), 2.15 (t, J = 7.4 Hz, 2H), 1.38-1.27 (m, 2H),1.13-1.03 (m, 2H), 0.66 (t, J = 7.0 Hz, 1.99 C 505.1 A 3H) 172

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl)- N-methyl- 1H NMR (500 MHz,DMSO-d6) δ 7.50 (br. s., 5H), 7.37 (t, J = 8.4 Hz, 1H), 6.75 (d, J = 8.3Hz, 2H), 5.03 (br. s., 2H), 3.71 (s, 6H), 3.06 (br. s., 3H), 2.17 (t, J= 7.6 Hz, 2H), 1.40-1.31 (m, 2H), 1.15-1.05 (m, 2H), 0.68 (t, J = 7.3Hz, 3H) 1.99 C 519.2 A benzamide 173

N-({5-[5- (2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl)- 2,4- dihydroxy-pyridin- 3-yl]- 1,3,4- oxadiazol- 2-yl} methyl) benzamide 1H NMR (500MHz, DMSO-d6) δ 7.90 (d, J = 8.0 Hz, 2H), 7.65-7.48 (m, 3H), 7.40-7.29(m, 1H), 6.72 (d, J = 8.3 Hz, 2H), 4.78 (d, J = 4.7 Hz, 2H), 3.94 (s,2H), 3.68 (s, 6H), 0.98 (t, J = 7.0 Hz, 3H) methylene obscured by waterpeak. 1.86 C 507.1 A 174

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl)- 3-methyl- butanamide 1H NMR (500MHz, DMSO-d6) δ 7.33 (t, J = 8.4 Hz, 1H), 6.71 (d, J = 8.3 Hz, 2H), 4.54(d, J = 4.7 Hz, 2H), 3.68 (s, 6H), 2.12 (br. s., 2H), 2.05-1.95 (m, 3H),1.39-1.28 (m, 2H), 1.13-1.01 (m, 2H), 0.89 (d, J = 6.1 Hz, 6H), 0.65 (t,J = 7.2 Hz, 3H) 1.99 C 485.1 A 175

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl) acetamide 1H NMR (500 MHz,DMSO-d6) δ 7.34 (t, J = 8.1 Hz, 1H), 6.71 (d, J = 8.5 Hz, 2H), 4.54 (d,J = 5.2 Hz, 2H), 3.68 (s, 6H), 2.13 (t, J = 7.0 Hz, 2H), 1.94- 1.81 (m,3H), 1.32 (t, J = 7.4 Hz, 2H), 1.14-0.96 (m, 2H), 0.65 (t, J = 7.0 Hz,3H) 1.81 C 443.1 A 176

N-({5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} methyl)- 2,2,2- trifluoro- acetamide 1HNMR (500 MHz, DMSO-d6) δ 7.35 (t, J = 8.4 Hz, 1H), 6.72 (d, J = 8.3 Hz,2H), 4.75 (d, J = 5.8 Hz, 2H), 3.68 (s, 6H), 2.21-2.08 (m, 2H),1.38-1.28 (m, 2H), 1.14-0.98 (m, 2H), 0.65 (t, J = 7.4 Hz, 3H) 1.95 C497.0 B 178

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-N- (pyridin-2- ylmethyl) acetamide 1H NMR(500 MHz, DMSO-d6) δ 11.99 (s, 1H), 11.91 (s, 1H), 8.24 (d, J = 7.0 Hz,1H), 7.54 (d, J = 9.2 Hz, 1H), 7.40-7.28 (m, 2H), 6.81-6.62 (m, 2H),4.15 (s, 2H), 3.69 (s, 6H), 2.53-2.49 (m, 4H), 2.17 (t, J = 7.5 Hz, 2H),1.44-1.21 (m, 2H), 1.14-1.04 (m, 2H), 0.66 (t, J = 7.2 Hz, 3H) 1.80 A520.0 B 179

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-N- methyl- acetamide 1H NMR (500 MHz,DMSO-d6) δ 8.26 (d, J = 5.0 Hz, 1H), 7.37 (t, J = 8.3 Hz, 1H), 6.74 (d,J = 8.5 Hz, 2H), 3.94 (s, 2H), 3.70 (s, 6H), 2.66 (d, J = 4.7 Hz, 3H),2.16 (t, J = 7.7 Hz, 2H), 1.41-1.30 (m, 2H), 1.15-1.03 (m, 2H), 0.67 (t,J = 7.4 Hz, 3H) 0.97 D 443.4 A 180

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} acetamide 1H NMR (500 MHz, DMSO-d6) δ7.77 (br. s., 1H), 7.46- 7.25 (m, 2H), 6.74 (d, J = 8.3 Hz, 1H), 3.93(s, 2H), 3.70 (s, 6H), 2.16 (t, J = 7.7 Hz, 2H), 1.34 (quin, J = 7.4 Hz,2H), 1.16-1.05 (m, 2H), 0.67 (t, J = 7.3 Hz, 3H) 1.75 C 429.1 B 181

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-N- (propan- 2-yl) acetamide 1H NMR (500MHz, DMSO-d6) δ 8.23 (d, J = 7.7 Hz, 1H), 7.37 (t, J = 8.5 Hz, 1H), 6.74(d, J = 8.3 Hz, 2H), 3.91 (s, 2H), 3.86 (dd, J = 13.3, 6.5 Hz, 1H), 3.71(s, 6H), 2.16 (t, J = 7.7 Hz, 2H), 1.37-1.28 (m, 2H), 1.16-1.01 (m, 8H),0.67 (t, J = 7.2 Hz, 3H) 0.84 D 471.5 A 182

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-N,N- dimethyl- acetamide 1H NMR (500 MHz,DMSO-d6) δ 7.37 (t, J = 8.5 Hz, 1H), 6.74 (d, J = 8.3 Hz, 2H), 4.29 (s,2H), 3.71 (s, 6H), 3.09 (s, 3H), 2.89 (s, 3H), 2.16 (t, J = 7.4 Hz, 2H),1.41- 1.28 (m, 2H), 1.14- 1.04 (m, 2H), 0.67 (t, J = 7.3 Hz, 3H) 0.80 D457.5 A 183

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-N-(4- methoxy- phenyl) acetamide 1H NMR(500 MHz, DMSO-d6) δ 7.52 (d, J = 8.8 Hz, 2H), 7.36 (t, J = 8.4 Hz, 1H),6.92 (d, J = 9.1 Hz, 2H), 6.73 (d, J = 8.5 Hz, 2H), 4.17 (s, 2H), 3.78-3.63 (m, 9H), 2.15 (t, J = 7.6 Hz, 2H), 1.38-1.27 (m, 2H), 1.16-1.02 (m,2H), 0.67 (t, J = 7.3 Hz, 3H) 0.88 D 535.4 B 184

4-(2-{5- [6-butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl} acetyl) piperazin- 2-one 1H NMR (500 MHz,DMSO-d6) δ 7.35 (t, J = 8.3 Hz, 1H), 6.73 (d, J = 8.5 Hz, 2H), 4.36 (d,J = 19.3 Hz, 2H), 4.20 (s, 1H), 3.98 (s, 1H), 3.74 (t, J = 5.2 Hz, 1H),3.70 (s, 6H), 3.64 (t, 1H), 3.22 (br. s., 2H), 2.15 (t, J = 7.7 Hz, 2H),1.34 (quin, J = 7.5 Hz, 2H), 1.15-1.03 (m, 0.75 D 512.4 A 2H), 0.67 (t,J = 7.3 Hz, 3H) 185

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-1- (4-methyl- piperazin- 1H NMR (500 MHz,DMSO-d6) δ 7.37 (t, J = 8.4 Hz, 1H), 6.74 (d, J = 8.3 Hz, 2H), 4.32 (s,2H), 3.71 (s, 6H), 3.54 (d, J = 4.1 Hz, 4H), 2.42 (br. s., 2H), 2.33(br. s., 2H), 2.23 (s, 3H), 2.16 (t, J = 7.6 Hz, 2H), 1.46-1.29 (m, 2H),1.18-1.04 (m, 2H), 0.67 (t, J = 0.70 D 512.5 B 1-yl) 7.3 Hz, 3H)ethan-1-one 186

N-benzyl-2- {5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy-pyridin- 3-yl]- 1,3,4- oxadiazol- 2-yl} acetamide 1H NMR (500 MHz,DMSO-d6) δ 7.45- 7.33 (m, 5H), 7.30- 7.23 (m, 1H), 6.74 (d, J = 8.3 Hz,2H), 4.35 (d, J = 5.5 Hz, 2H), 4.05 (s, 2H), 3.70 (s, 6H), 2.17 (t, J =7.4 Hz, 2H), 1.40-1.29 (m, 2H), 1.16-1.03 (m, 2H), 0.67 (t, J = 7.3 Hz,3H) 0.89 D 519.4 A 187

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-N- ethyl- acetamide 1H NMR (500 MHz,DMSO-d6) δ 7.35 (t, J = 8.4 Hz, 1H), 6.72 (d, J = 8.5 Hz, 2H), 3.92 (s,2H), 3.69 (s, 6H), 3.19- 3.05 (m, 2H), 2.15 (t, J = 7.6 Hz, 2H),1.43-1.27 (m, 2H), 1.14-0.96 (m, 5H), 0.65 (t, J = 7.3 Hz, 3H) 0.83 D457.5 A 188

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-N- cyclo- propyl- acetamide 1H NMR (500MHz, DMSO-d6) δ 7.37 (t, J = 8.1 Hz, 1H), 6.75 (d, J = 8.3 Hz, 2H), 3.91(s, 2H), 3.71 (s, 6H), 2.69 (br. s., 1H), 2.25- 2.13 (m, 2H), 1.41- 1.26(m, 2H), 1.16- 1.03 (m, 2H), 0.71- 0.58 (m, 5H), 0.48 (br. s., 2H) 0.83D 469.5 A 189

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-N- propyl- acetamide 1H NMR (500 MHz,DMSO-d6) δ 7.35 (t, J = 8.3 Hz, 1H), 6.72 (d, J = 8.3 Hz, 2H), 3.93 (s,2H), 3.69 (s, 6H), 3.06 (q, J = 6.3 Hz, 2H), 2.15 (t, J = 7.4 Hz, 2H),1.50-1.41 (m, 2H), 1.37-1.24 (m, 2H), 1.13-1.00 (m, 2H), 0.87 (t, J =7.2 Hz, 3H), 0.65 (t, J = 7.3 Hz, 3H) 0.85 D 471.5 A 190

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-N- (2-fluoro- ethyl) acetamide 1H NMR(500 MHz, DMSO-d6) δ 7.34 (t, J = 8.3 Hz, 1H), 6.71 (d, J = 8.5 Hz, 2H),4.56-4.39 (m, 2H), 3.98 (s, 2H), 3.68 (s, 6H), 3.49- 3.37 (m, 2H), 2.13(br. s., 2H), 1.43- 1.27 (m, 2H), 1.13-1.02 (m, 2H), 0.65 (t, J = 7.2Hz, 3H) 0.82 D 475.4 A 191

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-N- (2,2- difluoro- ethyl) acetamide 1HNMR (500 MHz, DMSO-d6) δ 7.35 (t, J = 8.1 Hz, 1H), 6.72 (d, J = 8.5 Hz,2H), 6.22-5.88 (m, 1H), 4.04 (s, 2H), 3.69 (s, 6H), 3.56 (t, J = 16.4Hz, 2H), 2.15 (t, J = 7.6 Hz, 2H), 1.39-1.27 (m, 2H), 1.12-1.01 (m, 2H),0.65 (t, J = 7.4 Hz, 3H) 0.85 D 493.4 A 192

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-N- (2,2,2- trifluoro- ethyl) acetamide 1HNMR (500 MHz, DMSO-d6) δ 7.35 (t, J = 8.4 Hz, 1H), 6.72 (d, J = 8.3 Hz,2H), 4.08 (s, 2H), 4.02-3.90 (m, 2H), 3.69 (s, 6H), 2.14 (t, J = 7.4 Hz,2H), 1.33 (t, J = 7.4 Hz, 2H), 1.14-0.99 (m, 2H), 0.65 (t, J = 7.3 Hz,3H) 0.87 D 511.4 A 193

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-N- (2-methoxy- ethyl) acetamide 1H NMR(500 MHz, DMSO-d6) δ 7.35 (t, J = 8.4 Hz, 1H), 6.72 (d, J = 8.3 Hz, 2H),3.96 (s, 2H), 3.69 (s, 6H), 3.38 (d, J = 5.5 Hz, 4H), 3.27 (s, 3H), 2.15(t, J = 7.3 Hz, 2H), 1.33 (t, J = 7.4 Hz, 2H), 1.15-1.03 (m, 2H), 0.65(t, J = 6.9 Hz, 3H) 0.81 D 487.5 B 194

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-1- (pyrrolidin- 1-yl) ethan-1-one 1H NMR(500 MHz, DMSO-d6) δ 7.37 (t, J = 8.5 Hz, 1H), 6.74 (d, J = 8.5 Hz, 2H),4.22 (s, 2H), 3.71 (s, 6H), 3.58 (t, J = 6.6 Hz, 2H), 2.16 (t, J = 7.4Hz, 2H), 1.98-1.72 (m, 6H), 1.39-1.27 (m, 2H), 1.13-1.05 (m, 2H), 0.67(t, J = 7.2 Hz, 3H) 0.85 D 483.5 A 195

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-1- (piperidin- 1-yl) ethan-1-one 1H NMR(500 MHz, DMSO-d6) δ 7.35 (t, J = 8.1 Hz, 1H), 6.73 (d, J = 8.3 Hz, 2H),4.28 (s, 2H), 3.69 (s, 6H), 3.51- 3.39 (m, 4H), 2.15 (t, J = 7.7 Hz,2H), 1.59 (br. s., 4H), 1.47 (br. s., 2H), 1.36-1.25 (m, 2H), 1.14-1.01(m, 2H), 0.65 (t, J = 7.3 Hz, 3H) 0.89 D 497.5 A 196

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-1- (morpholin- 4-yl) ethan-1-one 1H NMR(500 MHz, DMSO-d6) δ 7.35 (t, J = 8.3 Hz, 1H), 6.73 (d, J = 8.0 Hz, 2H),4.31 (s, 2H), 3.72-3.64 (m, 6H), 3.61-3.44 (m, 8H), 2.14 (t, J = 7.3 Hz,2H), 1.38-1.27 (m, 2H), 1.14-1.01 (m, 2H), 0.65 (t, J = 7.2 Hz, 3H) 0.82D 499.4 A 197

N-butyl-2- {5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy-pyridin- 3-yl]- 1,3,4- oxadiazol- 2-yl} acetamide 1H NMR (500 MHz,DMSO-d6) δ 7.19 (t, J = 8.1 Hz, 1H), 6.61 (d, J = 8.3 Hz, 2H), 3.73 (s,2H), 3.63 (s, 6H), 3.13- 3.04 (m, 2H), 1.93 (t, J = 7.3 Hz, 2H), 1.42(quin, J = 7.0 Hz, 2H), 1.36-1.23 (m, 6H), 1.14-1.02 (m, 2H), 0.89 (t, J= 7.2 Hz, 3H), 0.67 (t, J = 7.4 Hz, 3H) 0.94 D 485.4 A 198

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-N- pentyl- acetamide 1H NMR (500 MHz,DMSO-d6) δ 8.28 (br. s., 1H), 7.39- 7.24 (m, 1H), 6.72 (d, J = 7.7 Hz,2H), 3.92 (br. s., 2H), 3.68 (br. s., 6H), 3.09 (br. s., 2H), 2.14 (br.s., 2H), 1.43 (br. s., 2H), 1.36-1.20 (m, 6), 1.08 (d, J = 7.2 Hz, 2H),0.86 (br. s., 3H), 0.73-0.59 (m, 3H) 0.97 D 499.4 B 199

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-1- (3-fluoro- azetidin- 1-yl) 1H NMR (500MHz, DMSO-d6) δ 7.35 (t, J = 8.3 Hz, 1H), 6.72 (d, J = 8.5 Hz, 2H),5.53-5.33 (m, 1H), 4.66-4.55 (m, 1H), 4.45-4.33 (m, 1H), 4.24 (d, J =14.6 Hz, 1H), 4.07 (d, J = 6.9 Hz, 2H), 4.03-3.90 (m, 1H), 3.68 (s, 6H),2.20- 2.08 (m, 2H), 1.32 (d, J = 7.2 Hz, 2H), 1.12-1.03 (m, 2H), 0.87 D487.4 A ethan-1-one 0.65 (t, J = 7.0 Hz, 3H) 200

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-1- difluoro- azetidin- 1-yl) 1H NMR (500MHz, DMSO-d6) δ 7.34 (t, J = 8.2 Hz, 1H), 6.71 (d, J = 8.5 Hz, 2H), 4.75(t, J = 12.2 Hz, 2H), 4.34 (t, J = 12.4 Hz, 2H), 4.08 (s, 2H), 3.86 (br.s., 5H), 2.13 (t, J = 7.6 Hz, 2H), 1.29 (quin, J = 7.6 Hz, 2H),1.11-0.96 (m, 2H), 0.61 (t, J = 7.3 Hz, 3H) 0.91 D 505.3 A ethan-1-one201

2-{5-[6- butyl-5- (2,6- dimethoxy- phenyl)- 2,4- dihydroxy- pyridin-3-yl]- 1,3,4- oxadiazol- 2-yl}-N- (1,3- thiazol- 2-yl) acetamide 1H NMR(500 MHz, DMSO-d6) δ 7.53 (d, J = 3.3 Hz, 1H), 7.37 (t, J = 8.4 Hz, 1H),7.29 (d, J = 3.3 Hz, 1H), 6.74 (d, J = 8.5 Hz, 2H), 4.37 (s, 2H), 3.71(s, 6H), 2.17 (t, J = 7.7 Hz, 2H), 1.42- 1.29 (m, 2H), 1.14- 1.05 (m,2H), 0.67 (t, J = 7.3 Hz, 3H) 1.94 C 512.1 A 203

6-butyl-3- {3-[(4- chloro- phenyl) methyl]- 1,2,4- oxadiazol- 5-yl}-5-(2,6- dimethoxy- phenyl) pyridine- 2,4-diol 1H NMR (500 MHz, DMSO-d6) δ7.41- 7.31 (m, 5H), 6.72 (d, J = 8.5 Hz, 2H), 4.14 (s, 2H), 2.15 (t, J =7.3 Hz, 2H), 1.32 (t, J = 7.7 Hz, 2H), 1.08 (q, J = 7.0 Hz, 2H), 0.64(t, J = 7.3 Hz, 3H) 2.26 C 495.9 B 206

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-(5-{[5- (pyridin- 4-yl)- 1,3,4-oxadiazol- 2-yl] methyl}- 1,3,4- oxadiazol- 2-yl) pyridine-2,4- diol 1HNMR (500 MHz, DMSO-d6) δ 8.85 (d, J = 5.2 Hz, 2H), 7.96 (d, J = 5.0 Hz,2H), 7.34 (t, J = 8.1 Hz, 1H), 6.72 (d, J = 8.3 Hz, 2H), 4.99 (s, 2H),3.69 (s, 6H), 2.12 (t, J = 7.6 Hz, 2H), 1.40-1.28 (m, 2H), 1.14-1.03 (m,2H), 0.67 (t, J = 7.6 Hz, 3H) 0.77 D 531.3 A 207

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-(5-{[5- (pyridin- 2-yl)- 1,3,4-oxadiazol- 2-yl] methyl}- 1,3,4- oxadiazol- 2-yl) pyridine-2,4- diol 1HNMR (500 MHz, DMSO-d6) δ 8.79 (d, J = 4.4 Hz, 1H), 8.21 (d, J = 8.0 Hz,1H), 8.08 (t, J = 7.7 Hz, 1H), 7.70-7.61 (m, 1H), 7.35 (t, J = 8.5 Hz,1H), 6.72 (d, J = 8.3 Hz, 2H), 5.00 (s, 2H), 3.69 (s, 6H), 2.14 (t, J =7.6 Hz, 2H), 1.45-1.29 (m, 2H), 1.11-1.04 (m, 2H), 0.67 (t, J = 7.4 Hz,3H) 0.84 D 531.3 A 208

6-butyl-3- (5-{[5-(2- chloro- phenyl)- 1,3,4- oxadiazol- 2-yl] methyl)-1,3,4- oxadiazol- 2-yl)-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol1H NMR (500 MHz, DMSO-d6) δ 7.99 (d, J = 7.4 Hz, 1H), 7.79-7.73 (m, 1H),7.68 (t, J = 7.8 Hz, 1H), 7.61-7.51 (m, 1H), 7.36 (t, J = 8.3 Hz, 1H),6.73 (d, J = 8.5 Hz, 2H), 5.00 (s, 2H), 3.70 (s, 6H), 2.15 (t, J = 7.6Hz, 2H), 1.39-1.26 (m, 2H), 1.17-1.03 (m, 2H), 0.67 (t, J = 7.3 Hz, 3H)0.94 D 564.3 A 209

3-{5-[(5- benzyl- 1,3,4- oxadiazol- 2-yl) methyl]- 1,3,4- oxadiazol-2-yl}-6- butyl-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR(500 MHz, DMSO-d6) δ 7.41- 7.25 (m, 6H), 6.74 (d, J = 8.5 Hz, 2H), 4.85(s, 2H), 4.36- 4.25 (m, 2H), 3.70 (s, 6H), 2.16 (t, J = 7.6 Hz, 2H),1.35 (t, J = 7.4 Hz, 2H), 1.17-1.05 (m, 2H), 0.67 (t, J = 7.2 Hz, 3H)0.92 D 544.4 A 210

6-butyl-3- (5-{[5-(3- chloro- phenyl)- 1,3,4- oxadiazol- 2-yl] methyl}-1,3,4- oxadiazol- 2-yl)-5- (2,6- dimethoxy- phenyl) pyridine-2,4- diol1H NMR (500 MHz, DMSO-d6) δ 8.03- 7.97 (m, 2H), 7.75 (d, J = 7.7 Hz,1H), 7.69-7.63 (m, 1H), 7.36 (t, J = 8.3 Hz, 1H), 6.74 (d, J = 8.3 Hz,2H), 4.98 (s, 2H), 3.70 (s, 6H), 2.16 (br. s., 2H), 1.39-1.29 (m, 2H),1.16-1.04 (m, 2H), 0.67 (t, J = 7.2 Hz, 3H) 2.17 C 564.1 B 211

6-butyl-5- (2,6- dimethoxy- phenyl)- 3-(5-{[5- (pyridin- 3-yl)- 1,3,4-oxadiazol- 2-yl] methyl}- 1,3,4- oxadiazol- 2-yl) pyridine-2,4- diol 1HNMR (500 MHz, DMSO-d6) δ 9.19 (s, 1H), 8.83 (d, J = 5.0 Hz, 1H), 8.39(d, J = 8.5 Hz, 1H), 7.71-7.62 (m, 1H), 7.36 (t, J = 8.3 Hz, 1H), 6.74(d, J = 8.5 Hz, 2H), 5.00 (s, 2H), 3.70 (s, 6H), 2.16 (t, J = 7.6 Hz,2H), 1.40-1.24 (m, 2H), 1.13-1.00 (m, 2H), 0.66 (t, J = 7.3 Hz, 3H) 1.87C 531.1 B 213

3-[5-(1,2- benzoxazol- 3- ylmethyl)- 1,3,4- oxadiazol- 2-yl]-6- (ethoxy-methyl)- 5-(4- fluoro- 2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR(400 MHz, CDCl3) δ 7.92 (d, J = 7.9 Hz, 1H), 7.63-7.54 (m, 2H), 7.37 (m,1H), 6.39 (s, 1H), 6.36 (s, 1H), 4.75 (s, 2H), 4.13 (s, 2H), 3.73 (s,6H), 3.53 (m, 2H), 1.25 (t, J = 6.9 Hz, 3H) 1.96 C 523.1 A 214

3-{5-[(4- chloro- phenyl) methyl]- 1,3,4- oxadiazol- 2-yl}-6- (ethoxy-methyl)- 5-(4- fluoro- 2,6- dimethoxy- phenyl) pyridine-2,4- diol 1H NMR(400 MHz, CDCl3) δ 7.33 (m, 4H), 6.39 (s, 1H), 6.37 (s, 1H), 4.29 (s,2H), 4.14 (s, 2H), 3.73 (s, 6H), 3.53 (m, 2H), 1.25 (t, J = 6.9 Hz, 3H)2.10 C 516.1 A 215

1-({5-[6- (ethoxy- methyl)- 5-(4- fluoro- 2,6- dimethoxy- phenyl)- 2,4-dihydroxy- pyridin- 3-yl]- 1,3,4- oxadiazol- 2-yl} methyl) pyrrolidin-2-one 1H NMR (400 MHz, CDCl3) δ 6.43 (s, 1H), 6.41 (s, 1H), 4.87 (s,2H), 4.22 (s, 2H), 3.76 (s, 6H), 3.66 (m, 2H), 3.62- 3.55 (m, 2H), 2.58-2.52 (m, 2H), 2.23- 2.13 (m, 2H), 1.30 (t, J = 6.9 Hz, 3H) 1.69 C 489.1B 216

3-{5-[(6- chloro- pyridin- 3-yl) methyl]- 1,3,4- oxadiazol- 2-yl}-6-(ethoxy- methyl)- 5-(4- fluoro- 2,6- dimethoxy- phenyl) pyridine-2,4-diol 1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 2.2 Hz, 1H), 7.80 (m, 1H),7.38 (d, J = 8.4 Hz, 1H), 6.43 (s, 1H), 6.40 (s, 1H), 4.35 (s, 2H), 4.20(s, 2H), 3.75 (s, 6H), 3.58 (m, 2H), 1.29 (t, J = 7.0 Hz, 3H) 1.89 C517.1 A 220

3-[5-(1,2- benzoxazol- 3- ylmethyl)- 1,3,4- oxadiazol- 2-yl]-6- butyl-5-(3-fluoro- 2,6- dimethoxy- phenyl) pyridine-2,4- diol (isomer 1) 1H NMR(400 MHz, CDCl3) δ 7.78 (d, J = 7.9 Hz, 1H), 7.54-7.46 (m, 2H),7.31-7.24 (m, 1H), 7.06 (m, 1H), 6.54 (m, 1H), 4.65 (s, 2H), 4.01-3.91(m, 2H), 3.74 (m, 3H), 3.64 (s, 3H), 2.25 (m, 2H), 0.70 (t, J = 7.2 Hz,3H) 2.09 C 521.1 B 221

3-[5-(1,2- benzoxazol- 3- ylmethyl)- 1,3,4- oxadiazol- 2-yl]-6- butyl-5-(3-fluoro- 2,6- dimethoxy- phenyl) pyridine-2,4- diol (isomer 2) 1H NMR(400 MHz, CDCl3) δ 7.78 (d, J = 7.9 Hz, 1H), 7.54-7.48 (m, 2H),7.32-7.25 (m, 1H), 7.05 (m, 1H), 6.54 (m, 1H), 4.65 (s, 2H), 4.01-3.91(m, 2H), 3.74 (m, 3H), 3.64 (s, 3H), 2.25 (m, 2H), 0.70 (t, J = 7.3 Hz,3H) 2.09 C 521.1 A 225

3-[5-(1,2- benzoxazol- 3- ylmethyl)- 1,3,4- oxadiazol- 2-yl]-6- butyl-5-(2,4,6- trimethyl- phenyl) pyridine-2,4- diol 1H NMR (500 MHz, DMSO-d6)δ 11.86 (br. s., 1H), 7.99 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 8.5 Hz,1H), 7.74-7.68 (m, 1H), 7.44 (t, J = 7.3 Hz, 1H), 6.96 (s, 2H), 4.95 (s,2H), 3.35 (br. s., 23H), 2.52 (br. s., 6H), 2.28 (s, 3H), 2.15 (t, J =7.6 Hz, 2H), 1.40-1.31 (m, 2H), 1.18-1.08 (m, 2H), 0.71 (t, J = 7.2 Hz,3H) 2.29 A 485.3 B 226

3-[5-(1,2- benzoxazol- 3- ylmethyl)- 1,3,4- oxadiazol- 2-yl]-6- butyl-5-(2,6- diethyl- phenyl) pyridine-2,4- diol 1H NMR (400 MHz, CDCl3) δ12.34 (br. s., 1H), 10.84 (br. s., 1H), 7.86 (d, J = 7.9 Hz, 1H),7.61-7.53 (m, 2H), 7.40-7.31 (m, 2H), 7.21 (d, J = 7.7 Hz, 2H), 4.71 (s,2H), 2.38 (q, J = 7.6 Hz, 4H), 2.30-2.22 (m, 2H), 1.51 (dt, J = 15.6,7.7 Hz, 2H), 1.28- 1.20 (m, 2H), 1.11 (t, J = 7.6 Hz, 6H), 0.77 (t, J =7.4 Hz, 3H) 1.12 D 499.4 A 228

5-(2,6- dimethoxy- phenyl)- 6-(ethoxy- methyl)- 3-(5-{[1,2] oxazolo[4,5-b] pyridin-3- ylmethyl}- 1,3,4- oxadiazol- 2-yl) pyridine-2,4- diol1H NMR (500 MHz, DMSO-d6) δ 8.77 (d, J = 4.3 Hz, 1H), 8.34 (d, J = 8.5Hz, 1H), 7.75 (dd, J = 8.5, 4.3 Hz, 1H), 7.35 (t, J = 8.2 Hz, 1H), 6.72(d, J = 8.2 Hz, 2H), 4.94 (s, 2H), 3.94 (s, 2H), 3.69 (s, 6H), 3.28 (q,J = 6.9 Hz, 2H), 1.00 (t, J = 6.9 Hz, 3H) 1.21 A 506.2 A

Example 230.3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-[(ethylamino)methyl]pyridine-2,4-diol

Compound 230a. tert-butyl(2-1H-imidazol-1-yl)-2-oxoethyl)(ethyl)carbamate

To a solution of 2-((tert-butoxycarbonyl)(ethyl)amino)acetic acid (200mg, 0.98 mmol) in THF (2 mL) was added CDI (180 mg, 1.1 mmol) and thereaction mixture stirred for 18 h. The reaction mixture was diluted withwater and extracted with EtOAc (3×). The combined extracts were dried(MgSO₄) filtered and concentrated under reduced pressure to generateCompound 230a (220 mg, 0.87 mmol, 88% yield) as a yellow oil. LCMS(Method E) Rt=1.58 min, m/z=252.2 (M−H).

Compound 230b. ethyl4-((tert-butoxycarbonyl)(ethyl)amino)-2-(2,6-dimethoxyphenyl)-3-oxobutanoate

To a solution of Compound 1a (0.90 g, 4.0 mmol) in THF (5 mL) at −78° C.was added dropwise 1M LiHMDS in THF (5.6 mL, 5.6 mmol) and the reactionmixture stirred for 10 min then allowed to warm to room temperature andstirred for 1 h. The reaction mixture was cooled back to −78° C. then a2M solution of diethylzinc in hexane (2.8 mL, 5.6 mmol) was addeddropwise. The reaction mixture was stirred for 10 min then allowed towarm to −20° C. A solution of Compound 230a (1.2 g, 4.8 mmol) in THF (1mL) was added dropwise, and the reaction mixture stirred at −20° C. for20 min then quenched by the addition of 1N HCl. The reaction mixture wasextracted with DCM (2×) and the organic extracts were dried (MgSO₄)filtered and concentrated under reduced pressure. The residue waspurified by silica gel chromatography eluting with 0 to 30%EtOAc/hexanes to give Compound 230b (0.81 g, 2.0 mmol, 49% yield) as awhite solid. LCMS (Method E) Rt=1.99 min, m/z=410.3 (M+H).

Compound 230c. tert-butylN-[(5-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-3-(2,6-dimethoxyphenyl)-4,6-dihydroxypyridin-2-yl)methyl]-N-ethylcarbamate

Compound 230c was prepared from Compound 230b as described in thegeneral procedure given for Example 1 in 5% overall yield. LCMS (MethodA) Rt=1.76 min, m/z=598.4 (M+H). ¹H NMR (500 MHz, DMSO-d6) δ 8.53 (s,1H), 8.03-7.87 (m, 1H), 7.54 (d, J=8.2 Hz, 1H), 7.33 (t, J=8.2 Hz, 1H),6.70 (d, J=8.2 Hz, 2H), 4.54 (s, 2H), 3.95 (br. m, 1H), 3.72 (br.m.,2H), 2.78 (br. m., 2H), 2.51 (br. s., 6H), 1.26 (s, 4H), 1.30 (s, 5H),0.77 (br. s., 3H).

Example 230.3-{5-[(5-chloropyridin-2-yl)methyl]-1,3,4-oxadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-[(ethylamino)methyl]pyridine-2,4-diol

To a solution of Compound 230b (13 mg, 0.022 mmol) in DCM (1 mL) wasadded TFA (0.1 mL) and the reaction mixture stirred for 24 h. Thereaction mixture was concentrated under reduced pressure and the residuepurified by preparative HPLC to give Example 230 (10 mg, 0.019 mmol, 85%yield) as a white solid. LCMS (Method A) Rt=0.95 min, m/z=498.1 (M+H).¹H NMR (500 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.97 (d, J=6.8 Hz, 1H), 7.55(d, J=8.3 Hz, 1H), 7.37 (t, J=8.3 Hz, 1H), 6.74 (d, J=8.3 Hz, 2H), 4.56(s, 2H), 2.55 (m, 8H), 2.47 (br. s., 2H), 0.89 (t, J=6.7 Hz, 3H). HumanAPJ cAMP EC₅₀ potency range A.

Example 231.3-{5-[(1,2-benzoxazol-3-yl)methyl]-1,3,4-thiadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol

Compound 231a.N′-(2-(benzo[d]isoxazol-3-yl)acetyl)-6-butyl-5-(2,6-dimethoxyphenyl)-2,4-dihydroxynicotinohydrazide

To a mixture of5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)-2,4-dihydroxynicotinohydrazide(80 mg, 0.22 mmol, prepared by the general procedures given forExample 1) and 2-(benzo[d]isoxazol-3-yl)acetic acid (47 mg, 0.26 mmol)in DCM (1 mL) was added and Hunig's base (0.058 mL, 0.33 mmol) followedby a 50% solution of T3P® in ethyl acetate (0.20 mL, 0.33 mmol) and thereaction mixture was stirred at room temperature for 1.5 h. The reactionmixture was concentrated under reduced pressure and the residue purifiedby preparative HPLC to give Compound 231a (82 mg, 0.16 mmol, 71% yield)as a white solid. LCMS (Method D) Rt=0.82 min, m/z=517.2 (M+H).

Example 231.3-{5-[(1,2-benzoxazol-3-yl)methyl]-1,3,4-thiadiazol-2-yl}-5-(2,6-dimethoxyphenyl)-6-(ethoxymethyl)pyridine-2,4-diol

To a solution of Compound 231a (82 mg, 0.16 mmol) in THF (2 mL) wasadded Lawesson's reagent (64 mg, 0.16 mmol) and the mixture was heatedat 75° C. for 1 h. The mixture was allowed to cool to room temperaturethen concentrated under reduced pressure. The residue was dissolved indioxane (1 mL) then Hunig's base (0.069 mL, 0.39 mmol) was addedfollowed by a 50% solution of T3P® in ethyl acetate (0.23 mL, 0.39 mmol)and the reaction mixture was heated at 90° C. for 0.5 h. The reactionmixture was allowed to cool to room temperature then concentrated underreduced pressure and the residue purified by preparative HPLC to giveExample 231 (56 mg, 0.11 mmol, 69% yield) as a white solid. LCMS (MethodA) Rt=2.013 min, m/z=521.0 (M+H). 1H NMR (500 MHz, DMSO-d6) δ 7.85 (d,J=7.9 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H), 7.48-7.32(m, 2H), 6.75 (d, J=8.5 Hz, 2H), 5.04 (s, 2H), 4.01 (s, 2H), 3.69 (s,6H), 3.28 (q, J=6.9 Hz, 2H), 1.00 (t, J=7.0 Hz, 3H). Human APJ cAMP EC₅₀potency range B.

Examples 232-235 were prepared by the general procedures given forExample 231.

Examples 236-245 were prepared by the general procedures given forExample 1.

Examples 246-251 were prepared by the general procedures given forExample 137.

Examples 252-273 were prepared by the general procedures given forExample 177.

Examples 274-276 were prepared by the general procedures given forExample 222.

LC/MS hAPJ Rt cAMP (min) EC₅₀ (nM) Method Potency Ex # Structure Name ¹HNMR M+H range 232

3-{5-[(5- chloropyridin-2- yl)methyl]-1,3,4- thiadiazol-2-yl}-5- (2,6-dimethoxyphenyl)- 6-(ethoxymethyl) pyridine-2,4-diol 1H NMR (500MHz,DMSO-d6) δ 8.58 (s, 1H), 7.92 (dd, J=8.3, 2.2 Hz, 1H), 7.53 (d, J=8.4Hz, 1H), 7.37 (t, J=8.4 Hz, 1H), 6.73 (d, J=8.4 Hz, 2H), 4.64 (s, 2H),3.99 (s, 2H), 3.89 - 3.71 (m, 3H), 3.66 (s, 3H), 3.26 (q, J=7.0 Hz, 2H),0.97 (t, J=6.9 Hz, 3H) 1.909 A 515.2 A 233

3-{5-[(5- chloropyridin-2- yl)methyl]-l,3,4- thiadiazol-2-yl}-6-cyclopentyl-5-(2,6- dimethoxyphenyl) pyridine-2,4-diol 1H NMR (500MHz,DMSO-d6) δ 8.62 (s, 1H), 7.95 (d, J=6.3 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H),7.35 (t, J=8.3 Hz, 1H), 6.73 (d, J=8.3 Hz, 2H), 4.66 (s, 2H), 3.67 (s,6H), 2.55 (s, 9H), 1.73 (br. s., 6H), 1.66 (br. s., 3H), 1.38 (br. s.,3H) 2.068 A 525.3 B 234

3-{5-[(4- chlorophenyl) methyl]- 1,3,4-thiadiazol-2- yl}-5-(2,6-dimethoxyphenyl)- 6-(ethoxymethyl) pyridine-2,4-diol 1H NMR (500MHz,DMSO-d6) δ 7.45 - 7.27 (m, 5H), 6.74 (d, J=8.5 Hz, 2H), 4.49 (s, 2H),3.99 (s, 2H), 3.68 (s, 6H), 3.26 (q, J=6.6 Hz, 2H), 0.98 (t, J=7.0 Hz,3H) 2.341 A 514.3 B 235

N-({5-[5-(2,6- dimethoxyphenyl)- 6-(ethoxymethyl)- 2,4-dihydroxypyridin-3- yl]-1,3,4-thiadiazol- 2-yl}methyl) pyridine-2-carboxamide 1HNMR (500MHz, DMSO-d6) δ 9.79 (t, J=6.0 Hz, 1H), 8.69 (d,J=4.3 Hz, 1H), 8.14-7.95 (m, 2H), 7.76 - 7.53 (m, 1H), 7.37 (t, J=8.3Hz, 1H), 6.74 (d, J=8.3 Hz, 2H), 4.91 (d, J=6.0 Hz, 2H), 3.98 (s, 2H),3.78 - 3.69 (m, 2H), 3.66 (s, 2H), 3.26 (q, J=7.0 Hz, 2H), 3.16 (s, 2H),0.97 (t, J=6.9 Hz, 3H) 1.656 A 524.1 B 236

6-butyl-3-{5-[(5- chloro-3- fluoropyridin-2- yl)methyl]-1,3,4-oxadiazol-2-yl}-5- (2,6- dimethoxyphenyl) pyridine-2,4-diol 1H NMR(500MHz, DMSO-d6) δ 8.49 (d, J=1.2 Hz, 1H), 8.18 (dd, J=9.5, 1.8 Hz,1H), 7.36 (t, J=8.4 Hz, 1H), 6.74 (d, J=8.2 Hz, 2H), 4.63 (s, 2H), 3.70(s, 6H), 2.15 (t, J=7.6 Hz, 2H), 1.33 (quin, J=7.5 Hz, 2H), 1.16 - 1.03(m, 2H), 0.66 (t, J=7.3 Hz, 3H) 1.80 A 515.0 A 237

3-{5-[(5-chloro-3- fluoropyridin-2- yl)methyl]-l,3,4- oxadiazol-2-yl}-5-(2,6- dimethoxyphenyl)- 6-(ethoxymethyl) pyridine-2,4-diol 1H NMR(500MHz, DMSO-d6) δ 8.50 (d, J=1.2 Hz, 1H),8.19 (dd, J=9.5, 1.8 Hz, 1H),7.38 (t, J=8.4 Hz, 1H), 6.74 (d, J=8.5 Hz, 2H), 4.64 (s, 2H), 3.97 (s,2H), 3.70 (s, 6H), 3.28 (q, J=7.0 Hz, 2H), 1.00(t, J=7.0Hz, 3H) 1.69 A517.1 A 238

3-{5-[(5- chloropyridin-2- yl)methyl]-1,3,4- oxadiazol-2-yl}-6-cyclopentyl-5-(2,6- dimethoxyphenyl) pyridine-2,4-diol 1H NMR (500MHz,DMSO-d6) δ 8.60- 8.51 (m, 1H), 7.97 (dd, J=8.3,2.1 Hz, 1H), 7.55 (d,J=8.4 Hz, 1H), 7.34 (t, J=8.4 Hz, 1H), 6.72 (d, J=8.4 Hz, 2H), 4.58 (s,2H), 3.68 (s, 6H), 1.71 (br. s., 6H), 1.63 (br. s., 3H), 1.37 (br. s.,2H) 1.722 A 509.3 A 239

3-{5-[(4- chlorophenyl) methyl]-1,3,4- oxadiazol-2-yl}- 6-cyclopentyl-5-(2,6- dimethoxyphenyl) pyridine-2,4-diol 1H NMR (500MHz, DMSO-d6) δ7.47 - 7.33 (m, 4H), 7.27 (t, J=8.3 Hz, 1H), 6.67 (d, J=8.2 Hz, 2H),4.30 (br. s., 2H), 2.55 (s, 6H), 1.67 (br. s., 5H), 1.58 (br. s., 2H),1.34 (br. s., 2H) 1.983 A 508.1 A 240

3-{5-[(5- chloropyridin-2- yl)methyl]-1,3,4- oxadiazol-2-yl}-5- (2,6-dimethoxyphenyl)- 6-[(2- methoxyethoxy) methyl]pyridine- 2,4-diol 1H NMR(500MHz, DMSO-d6) δ 11.37 (s, 1H), 8.57 (d, J=2.5 Hz, 1H), 7.98 (dd,J=8.4, 2.6 Hz, 1H), 7.56 (d, J=8.3 Hz, 1H), 7.37 (t, J=8.4 Hz, 1H), 6.74(d, J=8.5 Hz, 2H), 4.59 (s, 2H), 4.01 (s, 2H), 3.70 (s, 6H), 3.38 (dd,J=6.5, 3.4 Hz, 2H), 3.36 - 3.32 (m, 2H), 3.19 (s, 3H) 1.25 D 529.3 A 242

3-{5-[(1,2- benzoxazol-3- yl)methyl]-1,3,4- oxadiazol-2-yl}-5- (2,6-dimethoxyphenyl)- 6-[(2- methoxyethoxy) methyl]pyridine- 2,4-diol 1H NMR(500MHz, DMSO-d6) δ 11.79 (br. s., 1H), 11.41 (s, 1H), 7.97 (d, J=8.0Hz, 1H), 7.80 (d, J=8.8 Hz, 1H), 7.71 (d, J=7.2 Hz, 1H), 7.43 (t, J=7.3Hz, 1H), 7.40 - 7.32 (m, 1H), 6.73 (d, J=8.5 Hz, 2H), 4.94 (s, 2H), 4.01(s, 2H), 3.69 (s, 6H), 3.38 (br. s., 4H), 3.19 (s, 3H) 1.31 D 535.2 B243

5-(2,6- dimethoxyphenyl)- 6-(ethoxymethyl)- 3-{5- [(phenylamino)methyl]-1,3,4- oxadiazol-2- yl}pyridine- 2,4-diol 1H NMR (500MHz,DMSO-d6) δ 7.35 (t, J=8.2 Hz, 1H), 7.11 (t, J=7.8 Hz, 2H), 6.77 - 6.66(m, 4H), 6.61 (t, J=7.2 Hz, 1H), 4.60 (br. s., 2H), 3.94 (s, 2H), 3.69(s, 6H), 3.35 - 3.22 (m, 2H), 1.00 (t, J=7.0 Hz, 3H) 1.669 A 479.1 B 244

3-{5-[(4- chlorophenyl) methyl]-1,3,4- oxadiazol-2-yl}- 5-(2,6-dimethoxyphenyl)- 6-[(2- methoxyethoxy) methyl]pyridine- 2,4-diol 1H NMR(500MHz, DMSO-d6) δ 11.35 (s, 1H), 7.52-7.31 (m, 4H), 6.74 (d, J=8.5 Hz,2H), 4.40 (s, 2H), 4.01 (s, 3H), 3.70 (s, 6H), 3.41 - 3.30 (m, 4H), 3.19(s, 3H) 2.050 E 526.3 B 246

N-({5-[6-butyl-5- (2,5- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol-2-yl} methyl)benzamide 1H NMR (500MHz, DMSO-d6) δ9.35 (br. s., 1H), 7.88 (d, J=7.5 Hz, 2H), 7.64 - 7.41 (m, 3H), 6.97 -6.81 (m, 2H), 6.63 (br. s., 1H), 4.71 (d, J=4.5 Hz, 2H), 2.55 (s,6H),2.26- 1.97 (m,2H), 1.42- 1.28 (m,2H), 1.16-1.02 (m, 2H), 0.66 (t, J=7.2Hz, 3H) 1.51 A 505.0 A 247

N-[(5-{6-butyl-2,4- dihydroxy-5-[2- methoxy-5- (propan- 2-yl)phenyl]pyridin-3- yl}-1,3,4- oxadiazol- 2-yl)methyl] benzamide 1H NMR (500MHz,DMSO-d6) δ 9.34 (t, J=5.3 Hz, 1H), 7.90 (d, J=7.6 Hz, 2H), 7.63 - 7.45(m, 3H), 7.22 (d, J=8.1 Hz, 1H), 7.07- 6.90 (m, 2H), 4.78 (d, J=5.2 Hz,2H), 3.67 (s, 3H), 2.92 - 2.78 (m, 1H), 2.28-2.06 (m, 2H), 1.44- 1.31(m, 2H), 1.18 (t, J=5.9 Hz, 6H), 1.12 - 1.02 (m, 2H), 0.65 (t, J=7.2 Hz,3H) 2.09 A 517.1 A 248

3-{5-[(1,2- benzoxazol-3- yl)methyl]-1,3,4- oxadiazol-2-yl}-6-(ethoxymethyl)- 5-(2- methoxyphenyl) pyridine-2,4-diol 1H NMR (500MHz,DMSO-d6) δ 7.95 (d, J=7.9 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.74-7.65 (m,1H), 7.46- 7.35 (m, 2H),7.19- 7.12 (m, 1H), 7.08 (d, J=8.5 Hz, 1H),7.01 - 6.93 (m, 1H), 4.92 (s, 2H), 4.09 - 3.89 (m, 2H), 3.70 (s, 3H),3.28 (quin, J=6.7 Hz, 2H), 0.99 (t, J=7.0 Hz, 4H) 1.48 A 475.0 A 249

3-{5-[(4- chlorophenyl) methyl]-1,3,4- oxadiazol-2-yl}-6-(ethoxymethyl)- 5-(2- methoxyphenyl) pyridine-2,4-diol 1H NMR (500MHz,DMSO-d6) δ 7.50-7.31 (m, 5H), 7.18-6.89 (m, 3H), 4.36 (s, 2H), 4.09 -3.88 (m, 2H), 3.70 (s, 3H), 3.34 - 3.11 (m, 2H), 0.99 (t, J=6.9 Hz, 3H)1.71 A 468.2 A 250

N-({5-[6-butyl-5- (2,3- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}methyl) benzamide 1H NMR (500MHz, DMSO-d6)δ 9.33 (br. s., 1H), 7.90 (d, J=7.4 Hz, 2H), 7.60 - 7.46 (m, 4H),7.12-6.95 (m, 2H), 6.66 (d, 5=6.6 Hz, 1H), 4.72 (d, J=5.0 Hz, 2H), 3.80(s, 3H), 2.55 (s, 3H), 2.18-2.04 (m, 2H), 1.91 (s, 2H), 1.37 (d, J=6.9Hz, 2H), 1.15- 1.03 (m, 3H) 1.48 A 505.4 A 251

N-({5-[6- (ethoxymethyl)- 2,4-dihydroxy- 5-(2- methoxyphenyl)pyridin-3-yl]- 1,3,4-oxadiazol- 2-yl}methyl) benzamide 1H NMR (500MHz,DMSO-d6) δ 9.26 (t, J=5.5 Hz, 1H), 7.90 (d, J=7.6 Hz, 2H), 7.58 - 7.45(m, 4H), 7.30 - 7.21 (m, 1H), 7.06 - 6.87 (m, 3H), 4.68 (d, J=5.5 Hz,2H), 3.98 - 3.79 (m, 3H), 3.67 (s, 3H), 3.27 (q, 5=6.6 Hz, 2H), 1.07-0.90 (m, 3H) 1.30 A 477.0 A 252

2-{5-[6-butyl-5- (2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-(pyridin-3- yl)acetamide 1H NMR (500MHz,DMSO-d6) δ 10.78 (NH), 8.79 (br. s., 1H), 8.34 (br. s., 1H), 8.07 (d,J=7.9 Hz, 1H), 7.48-7.41 (m, 1H), 7.37 (t, J=8.5 Hz, 1H), 6.74 (d, J=8.5Hz, 2H), 4.28 (s, 2H), 3.70 (s, 6H), 2.16 (t, J=7.2 Hz, 2H), 1.42- 1.27(m, 2H), 1.15-1.02 (m, 2H), 0.66 (t, J=7.2 Hz, 3H) 1.40 A 506.2 A 253

2-{5-[5-(2,6- dimethoxyphenyl)- 6-(ethoxymethyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol-2-yl}- N-(1,3-thiazol-2- yl)acetamide 1H NMR(500MHz, DMSO-d6) δ 7.53 (d, J=3.0 Hz, 1H), 7.38 (t, J=8.4 Hz, 1H), 7.29(d, J=3.0 Hz, 1H), 6.75 (d, J=8.3 Hz, 2H), 4.37 (s, 2H), 3.97 (s, 2H),3.71 (s, 6H), 3.28 (q, J=6.9 Hz, 2H), 1.00 (t, J=7.0 Hz, 3H). 1.18 C514.1 A 254

N-[(1,3- benzothiazol- 2-yl)methyl]-2- {5-[6- butyl-5-(2,6-dimethoxyphenyl)- 2,4- dihydroxypyridin- 3-yl]-1,354- oxadiazol-2-yl}acetamide 1H NMR (500MHz, DMSO-d6) δ 9.43 - 9.30 (NH), 8.07 (d,J=7.9 Hz, 1H), 7.97 (d, J=7.9 Hz, 1H), 7.55 - 7.50 (m, 1H), 7.44 (t,J=7.5 Hz, 1H), 7.36 (t, J=8.2 Hz, 1H), 6.74 (d, J=8.5 Hz, 2H), 4.76 (d,J=5.8 Hz, 2H), 4.11 (s, 2H), 3.69 (s, 6H), 2.16 (t, J=7.5 Hz, 2H), 1.44-1.29 (m, 2H), 1.16-1.03 (m, 2H), 0.67 (t, J=7.3 Hz, 3H) 1.617 A 576.2 A255

2-{5-[6-butyl-5- (2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-[(pyridin- 3-yl)methyl] acetamide 1H NMR(500MHz, DMSO-d6) δ 8.92 (NH), 8.53 (s, 1H), 8.48 (d, J=4.3 Hz, 1H),7.74 (d, J=7.3 Hz, 1H), 7.44 - 7.26 (m, 2H), 6.73 (d, J=8.5 Hz, 2H),4.38 (d, J=5.5 Hz, 2H), 4.03 (s, 2H), 3.69 (s, 6H), 2.14 (d, J=7.3 Hz,2H), 1.41 -1.27(m, 2H), 1.13-1.04 (m, 2H), 0.67 (t, J=7.2 Hz, 3H) 1.358A 520.2 A 256

2-{5-[6-butyl-5- (2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-[(1,3- oxazol- 2-yl)methyl] acetamide 1HNMR (500MHz, DMSO-d6) δ 9.03 (NH), 8.06 (s, 1H), 7.36 (t, J=8.4 Hz, 1H),7.18 (s, 1H), 6.74 (d, J=8.5 Hz, 2H), 4.46 (d, J=5.8 Hz, 2H), 4.04 (s,2H), 3.70 (s, 6H), 2.15 (br. s., 2H), 1.40 - 1.29 (m, 2H), 1.15-1.03(m,2H), 0.67 (t, J=7.3 Hz, 3H) 1.596 B 510.2 A 257

2-{5-[6-butyl-5- (2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-[2-(4- sulfamoylphenyl) ethyl]acetamide1H NMR (500MHz, DMSO-d6) δ 8.47 (NH), 7.77 (d, J=7.9 Hz, 2H), 7.45 (d,J=7.6 Hz, 2H), 7.39- 7.28 (m, 1H), 6.78 - 6.63 (m, 2H), 3.93 (s, 2H),3.75 - 3.64 (m, 6H), 3.54 - 3.32 (m, 2H), 2.85 (t, J=7.0 Hz, 2H),2.23-2.11 (m, 2H), 1.41 -1.25 (m,2H), 1.16- 1.01 (m, 2H), 0.66 (t, J=7.2Hz, 3H) 1.862 A 612.1 A 258

2-{5-[6-butyl-5- (2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-[2-(2- chlorophenyl) ethyl]acetamide 1HNMR (500MHz, DMSO-d6) δ 8.48 (NR), 7.43 (d, J=7.6 Hz, 1H), 7.35 (d,J=5.2 Hz, 2H), 7.32- 7.23 (m, 2H), 6.74 (d, J=8.2 Hz, 2H), 3.92 (s, 2H),3.70 (s, 6H), 3.36 (d, J=6.4 Hz, 2H), 2.89 (t, J=6.9 Hz, 2H), 2.15 (t,J=7.3 Hz, 2H), 1.40- 1.27 (m, 2H), 1.19- 1.02 (m, 2H), 0.67 (t, J=7.2Hz, 3H) 1.806 A 567.1 A 259

2-{5-[6-butyl-5- (2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-[(3- chlorophenyl) methyl]acetamide 1HNMR (500MHz, DMSO-d6) δ 8.90 (NH), 7.43 - 7.21 (m, 5H), 6.73 (d, J=8.5Hz, 2H), 4.35 (d, J=5.5 Hz, 2H), 4.05 (s, 2H), 3.69 (s, 6H), 2.15 (t,J=7.0 Hz, 2H), 1.43 - 1.27 (m, 2H), 1.18-0.99 (m, 2H), 0.67 (t, J=7.2Hz, 3H) 1.749 A 553.1 A 260

N-benzyl-2-{5-[6- butyl-5-(2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N- methylacetamide 1H NMR (500MHz,DMSO-d6) δ 7.57 - 7.23 (m, 6H), 6.72 (d, J=8.2 Hz, 2H), 4.55 (s, 2H),4.35 (s, 2H), 3.69 (s, 6H), 2.12 (t, J=7.3 Hz, 2H), 1.92 (s, 3H), 1.39-1.26 (m, 2H), 1.14-1.00 (m, 2H), 0.67 (t, J=7.2 Hz, 3H) 1.701 A 533.2 A261

2-{5-[6-butyl-5- (2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-methyl- N-(2-phenylethyl) acetamide 1HNMR (500MHz, DMSO-d6) δ 7.43 -7.15 (m, 6H), 6.74 (d, J=7.6 Hz, 2H), 4.04(s, 2H), 3.70 (br. S., 6H), 2.93 (t, J-7.3 Hz, 2H), 2.79 (t, J=7.3 Hz,2H), 2.17 (m, 2H), 1.34 (m, 2H), 1.09 (d, J=6.7 Hz, 2H), 0.66 (t, J=7.2Hz, 3H) 1.778 A 546.9 A 262

2-{5-[6-butyl-5- (2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-(prop-2- yn-1-yl)acetamide 1H NMR(500MHz, DMSO-d6) δ 8.81 (NH), 7.37 (t, J=8.2 Hz, 1H), 6.74 (d, J=8.5Hz, 2H), 4.00 (d, J=1.0 Hz, 2H), 3.93 (s, 2H), 3.70 (s, 6H), 3.18 (s,1H), 2.16 (t, J=7.5 Hz, 2H), 1.40- 1.28 (m, 2H), 1.14 - 1.04 (m, 2H),0.67 (t, J=7.2 Hz, 3H) 1.729 A 467.1 A 263

2-{5-[6-butyl-5- (2.6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-(3-methyl- 1H-pyrazol-5- yl)acetamide 1HNMR (500MHz, DMSO-d6) δ 7.36 (t, J=8.3 Hz, 1H), 6.73 (d, J=8.3 Hz, 2H),6.24 (br. s., 1H), 4.15 (s, 2H), 3.70 (s, 6H), 2.20 (s, 3H), 2.15 (t,J=1.0 Hz, 2H), 1.36- 1.27 (m, 2H), 1.10-1.01 (m, 2H), 0.66 (t, J=7.3 Hz,3H) 1.736 A 509.1 A 264

2-{5-[6-butyl-5- (2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-[(2- methylphenyl) methyl]acetamide 1HNMR (500MHz, DMSO-d6) δ 8.73 (NH), 7.37 (t, J=8.2 Hz, 1H), 7.32 - 7.27(m, 1H), 7.23 - 7.12 (m, 3H), 6.74 (d, J=8.5 Hz, 2H), 4.32 (d, J=5.2 Hz,2H), 4.04 (s, 2H), 3.70 (s, 6H), 2.29 (s, 3H), 2.16 (t, J=7.5 Hz, 2H),1.37- 1.26 (m, 2H), 1.17-0.98(m, 2H), 0.67 (t, J=7.2 Hz, 3H) 1.743 A533.2 A 265

2-{5-[6-butyl-5- (2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-[(2- chlorophenyl) methyl]acetamide 1HNMR (500MHz, DMSO-d6) δ 8.90 (NH), 7.46 (d, J=7.6 Hz, 2H), 7.40 - 7.25(m, 3H), 6.74 (d, J=8.2 Hz, 2H), 4.41 (d, J=5.8 Hz, 2H), 4.08 (s, 2H),3.70 (s, 5H), 2.16 (t, J=7.5 Hz, 2H), 1.39- 1.28 (m, 2H), 1.15- 0.99 (m,2H), 0.67 (t, J=7.2 Hz, 3H) 2.009 A 553.1 A 266

2-{5-[6-butyl-5- (2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-[(4- chlorophenyl) methyl]acetamide 1HNMR (500MHz, DMSO-d6) δ 8.90 NH), 7.49 - 7.30 (m, 5H), 6.74 (d, J=8.2Hz, 2H), 4.33 (d, J=5.5 Hz, 2H), 4.04 (s, 2H), 3.70 (s, 6H), 2.18 (t,J=1.0 Hz, 2H), 1.43 - 1.28 (m, J=7.0 Hz, 2H), 1.15-1.03 (m, J=7.0 Hz,2H), 0.67 (t, J=7.2 Hz, 3H) 1.750 A 553.3 A 267

2-{5-[6-butyl-5- (2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-[2-(4- chlorophenyl) ethyl]acetamide 1HNMR (500MHz, DMSO-d6) δ 8.41 (NH), 7.35 (d, J=7.9 Hz, 3H), 7.27 (d,J-7.9 Hz, 2H), 6.74 (d, J=8.5 Hz, 2H), 3.92 (br. s., 2H), 3.70 (s, 6H),3.33 (q, J=6.1 Hz, 2H), 2.75 (t, J=6.7 Hz, 2H), 2.16 (t, J=7.2 Hz, 2H),1.59- 1.49 (m, J=10.7 Hz, 2H), 1.39- 1.30 (m, 2H), 0.66 (t, J=7.3 Hz,3H) 1.834 A 567.1 A 268

2-{5-[6-butyl-5- (2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-[(pyridin- 4-yl)methyl] acetamide 1H NMR(500MHz, DMSO-d6) δ 8.99 (NH), 8.51 (d,J=4.9 Hz, 2H), 7.40 - 7.23 (m,3H), 6.71 (d, J=8.2 Hz, 2H), 4.37 (d, J=5.8 Hz, 2H), 4.04 (s, 2H), 3.68(s, 6H), 2.11 (t, J=7.0 Hz, 2H), 1.38- 1.27 (m, J=7.5, 7.5 Hz, 2H),1.16- 1.03 (m, 2H), 0.66 (t, J=7.2 Hz, 3H) 1.337 A 520.2 A 269

2-{5-[6-butyl-5- (2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-[(4- methoxyphenyl) methyl]acetamide 1HNMR (500MHz, DMSO-d6) δ 8.77 (NH), 7.37 (t, J=8.2 Hz, 1H), 7.24 (d,J=8.2 Hz, 2H), 6.91 (d, J=8.2 Hz, 2H), 6.74 (d, J=8.2 Hz, 2H), 4.27 (d,J=5.5 Hz, 214), 4.05 - 3.96 (m, 2H), 3.74 (s, 3H), 3.70 (s, 6H), 2.16(t, J=7.5 Hz, 2H), 1.43- 1.29 (m, J=7.3,7.3 Hz, 2H), 1.14-1.04 (m, 2H),0.67 (t, J=7.3 Hz, 3H) 1.701 A 549.1 A 270

2-{5-[6-butyl-5- (2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-{[4- (dimethylamino) phenyl]methyl}acetamide 1H NMR (500MHz, DMSO-d6) δ 8.68 (NH), 7.36 (t, J=8.4 Hz, 1H),7.13 (d, J=7.9 Hz, 2H), 6.80- 6.61 (m, J=17.2, 8.1 Hz, 4H), 4.21 (d,J=5.2 Hz, 2H), 3.98 (s, 2H), 3.70 (s, 6H), 2.87 (s, 6H), 2.16 (t, J=7.3Hz, 2H), 1.38- 1.28 (m,2H), 1.14-1.05 (m, 2H), 0.67 (t, J=7.2 Hz, 3H)1.694 A 562.2 A 271

2-{5-[6-butyl-5- (2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-[(5- methyl- 1,3,4-oxadiazol-2-yl)methyl] acetamide 1H NMR (500MHz, DMSO-d6) δ 9.10 (NH), 7.37 (t,J=8.2 Hz, 1H), 6.74 (d, J=8.2 Hz, 2H), 4.54 (d, J=5.5 Hz, 2H), 4.05 (s,2H), 3.69 (s, 6H), 2.48 (s, 3H), 2.16 (t, J=7.5 Hz, 2H), 1.38- 1.27 (m,2H), 1.15-0.99 (m, 3H), 0.66 (t, J=7.2 Hz, 4H) 1.652 A 525.2 A 272

2-{5-[6-butyl-5- (2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-{[3- (propan-2-yl)- 1,2-oxazol-5-yl]methyl} acetamide 1H NMR (500MHz, DMSO-d6) δ 9.02 (t, J=5.5 Hz, 1H),7.35 (t, J=8.2 Hz, 1H), 6.73 (d, J=8.2 Hz, 2H), 6.35 (s, 1H), 4.43 (d,J=5.5 Hz, 2H), 4.04 (s, 2H), 2.97 (dt, J=14.0,7.2 Hz, 1H), 2.15 (t,J=7.5 Hz, 2H), 1.38 - 1.29 (m, 2H), 1.21 (s, 3H), 1.20 (s, 3H), 1.14-1.03 (m, 2H), 0.66 (t, J=7.3 Hz, 3H) 1.603 A 552.2 A 273

2-{5-[6-buty]-5- (2,6- dimethoxyphenyl)- 2,4- dihydroxypyridin-3-yl]-1,3,4- oxadiazol- 2-yl}-N-[(4- sulfamoylphenyl) methyl]acetamide1H NMR (500MHz, DMSO-d6) 8 8.95 (NH), 7.80 (d, J=7.9 Hz, 2H), 7.50 (d,J=7.9 Hz, 2H), 7.35 (t, J=1.0 Hz, 1H), 6.73 (d, J=8.5 Hz, 2H), 4.41 (d,J=5.8 Hz, 2H), 4.05 (s, 2H), 3.69 (s, 6H), 2.15 (t, J=7.6 Hz, 2H), 1.38-1.27 (m, J=7.3, 7.3 Hz, 2H), 1.13-1.03 (m, 2H), 0.67 (t, J=7.3 Hz, 3H)1.463 A 598.3 B 274

3-{5-[(5- chloropyridin-2- yl)methyl]-1,3,4- oxadiazol-2-yl}-6-(ethoxymethyl)- 5-(2-hydroxy-6- methoxyphenyl) pyridine-2,4-diol 1H NMR(400MHz, CDCl₃) δ 8.62-8.37 (m, 1H), 7.73 -7.55 (m, 1H), 7.27 (m, 2H),6.79 - 6.63 (m,lH), 6.56-6.38 (m, 1H), 4.40 - 4.26 (m,2H), 4.20 - 4.12(m, 2H), 3.70 (s, 3H), 3.62 - 3.39 (m, 2H), 1.38 - 1.26 (m, 3H) 0.80 D485.0 A 275

3-{5-[(5- chloropyridin-2- yl)methyl]-1,3,4- oxadiazol-2-yl}-6-(ethoxymethyl)- 5-(2-hydroxy-6- methoxyphenyl) pyridine-2,4-diol 1H NMR(400MHz, CDCl₃) δ 8.40 (br. s., 1H), 7.53 (br. s., 1H), 7.36 - 7.09 (m,2H), 6.59 (d, J=8.4 Hz, 1H), 6.43 (d, J=8.1 Hz, 1H), 4.28 (br. s.,2H),4.14(q, J=15.3 Hz, 2H), 3.53 - 3.38 (m, 2H), 2.75 (br. s., 2H), 1.22-1.15 (m, 3H) 0.80 D 485.0 B 276

3-{5-[(5- chloropyridin-2- yl)methyl]-l,3,4- oxadiazol-2-yl}- 5-(2,6-dihydroxyphenyl)- 6-(ethoxymethyl) pyridine-2,4-diol 1H NMR (500MHz,DMSO-d6) δ 12.06- 11.78 (m, 1H), 11.40- 11.21 (m, 1H), 9.26-9.05 (m,2H), 8.69-8.45 (m, 1H),8.11 - 7.82 (m, 1H), 7.64 - 7.49 (m, 1H), 7.04 -6.90 (m, 1H), 6.37 (d, J=8.0 Hz, 2H), 4.60 (s, 2H), 4.04 (s, 2H), 3.33(d, J=6.9 Hz, 2H), 1.03 (t, J=6.9 Hz, 3H) 0.71 D 471.0 B

What is claimed is:
 1. A method of treating cardiovascular diseases,comprising administering to a patient in need there of a therapeuticallyeffective amount of the pharmaceutical composition of a compound ofFormula (I):

a tautomer, or a pharmaceutically acceptable salt thereof, wherein: alkis C₁₋₆ alkyl substituted with 0-5 R^(e); ring A is independentlyselected from the group consisting of:

ring B is independently selected from the group consisting of:

and 6-membered heteroaryl; R¹ is independently selected from the groupconsisting of: H, halogen, NO₂, —(CH₂)_(n)OR^(b),(CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a),—(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂)_(n)NR^(a)C(═O)R^(b),—(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a), —(CH₂)_(n)NR^(a)C(═O)OR^(b),—(CH₂)_(n)OC(═O)NR^(a)R^(a), —(CH₂)_(n)C(═O)OR^(b),—(CH₂)_(n)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a),—(CH₂)_(n)NR^(a)S(O)_(p)R^(c), C₁₋₄ alkyl substituted with 0-3 R^(e),—(CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R² is independentlyselected from the group consisting of: C₁₋₅ alkyl substituted with 0-3R^(e); C₂₋₅ alkenyl substituted with 0-3 R^(e), and C₃₋₆ cycloalkylsubstituted with 0-3 R^(e); provided when R² is C₁₋₅ alkyl, the carbonatom except the one attached directly to the pyridine ring may bereplaced by O, N, and S; R³ is independently selected from the groupconsisting of: (1) —(CR⁴R⁴)_(r)C(═O)OC₁₋₄ alkyl substituted with 0-5R^(e), (2) —(CR⁴R⁴)_(r)NR^(a)R^(a), (3) —(CR⁴R⁴)_(r)C(═O)NR^(a)R^(a),(4) —(CR⁴R⁴)_(r)NR^(a)C(═O)C₁₋₄alkyl substituted with 0-5 R^(e), (5)—(CR⁴R⁴)_(r)NR^(a)C(═O)(CR⁴R⁴)_(n)OC₁₋₄alkyl substituted with 0-5 R^(e),(6) —(CR⁴R⁴)_(r)—R⁵, (7) —(CR⁴R⁴)_(r)—OR⁵, (8)—(CR⁴R⁴)_(r)NR^(a)C(═O)(CR⁴R⁴)_(n)R⁵, and (9)—(CR⁴R⁴)_(r)C(═O)NR^(a)(CR⁴R⁴)_(n)R⁵; R⁴ is independently selected fromthe group consisting of: H, halogen, NR^(a)R^(a), OC₁₋₄ alkyl, and C₁₋₄alkyl; or R⁴ and R⁴ together with the carbon atom to which they are bothattached form C₃₋₆ cycloalkyl substituted with 0-5 R^(e); R⁵ isindependently selected from the group consisting of: —(CH₂)_(n)—C₃₋₁₀carbocycle and —(CH₂)_(n)-heterocycle, each substituted with 0-3 R⁶; R⁶is independently selected from: H, halogen, ═O, —(CH₂)_(n)OR^(b),(CH₂)_(n)S(O)_(p)R_(c), —(CH₂)_(n)C(═O)R^(b), —(CH₂)_(n)NR^(a)R^(a),—(CH₂)_(n)CN, —(CH₂)_(n)C(═O)NR^(a)R^(a), —(CH₂)_(n)NR^(a)C(═O)R^(b),—(CH₂)_(n)NR^(a)C(═O)NR^(a)R^(a), —(CH₂)_(n)NR^(a)C(═O)OR^(b),—(CH₂)_(n)OC(═O)NR^(a)R^(a), —(CH₂)_(n)C(═O)OR^(b),—(CH₂)_(n)S(O)_(p)NR^(a)R^(a), —(CH₂)_(n)NR^(a)S(O)_(p)NR^(a)R^(a),—(CH₂)_(n)NR^(a)S(O)_(p)R^(c), C₁₋₅ alkyl substituted with 0-3 R^(e),(CH₂)_(n)—C₃₋₆ carbocyclyl substituted with 0-3 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-3 R^(e); R^(a) isindependently selected from the group consisting of: H, C₁₋₆ alkylsubstituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5 R^(e),C₂₋₆ alkynyl substituted with 0-5 R^(e), —(CH₂)_(n)—C₃₋₁₀carbocyclylsubstituted with 0-5 R^(e), and —(CH₂)_(n)-heterocyclyl substituted with0-5 R^(e); or R^(a) and R^(a) together with the nitrogen atom to whichthey are both attached form a heterocyclic ring substituted with 0-5R^(e); R^(b) is independently selected from the group consisting of: H,C₁₋₆ alkyl substituted with 0-5 R^(e), C₂₋₆ alkenyl substituted with 0-5R^(e), C₂₋₆ alkynyl substituted with 0-5 R^(e),—(CH₂)_(n)—C₃₋₁₀carbocyclyl substituted with 0-5 R^(e), and—(CH₂)_(n)-heterocyclyl substituted with 0-5 R^(e); R^(c) isindependently selected from the group consisting of: C₁₋₆ alkylsubstituted with 0-5 R^(e), C₂₋₆alkenyl substituted with 0-5 R^(e),C₂₋₆alkynyl substituted with 0-5 R^(e), C₃₋₆carbocyclyl, andheterocyclyl; R^(e) is independently selected from the group consistingof: C₁₋₆ alkyl substituted with 0-5 R_(f), C₂₋₆ alkenyl, C₂₋₆ alkynyl,—(CH₂)_(n)—C₃₋₆ cycloalkyl, —(CH₂)_(n)—C₄₋₆ heterocyclyl,—(CH₂)_(n)-aryl, —(CH₂)_(n)-heteroaryl, F, Cl, Br, CN, NO₂, ═O, CO₂H,—(CH₂)_(n)OR_(f), S(O)_(p)R^(f), C(═O)NR^(f)R^(f), NR^(f)C(═O)R^(f),S(O)_(p)NR^(f)R^(f), NR^(f)S(O)_(P)R^(f), NR^(f)C(═O)OR^(f),OC(═O)NR^(f)R^(f), and —(CH₂)_(n)NR^(f)R^(f); R^(f) is independentlyselected from the group consisting of: H, F, Cl, Br, CN, OH, C₁₋₅alkyl(optimally substituted with halogen and OH), C₃₋₆ cycloalkyl, andphenyl, or R^(f) and R^(f) together with the nitrogen atom to which theyare both attached form a heterocyclic ring optionally substituted withC₁₋₄alkyl; n is independently selected from zero, 1, 2, and 3; r isindependently selected from zero, 1, 2, and 3; and p is independentlyselected from zero, 1, and
 2. 2. The method of claim 1 wherein saidcardiovascular diseases are coronary heart disease, stroke, heartfailure, systolic heart failure, diastolic heart failure, diabetic heartfailure, heart failure with preserved ejection fraction, cardiomyopathy,myocardial infarction, left ventricular dysfunction, left ventriculardysfunction after myocardial infarction, cardiac hypertrophy, myocardialremodeling, myocardial remodeling after infarction or after cardiacsurgery and valvular heart diseases.